Methods of treating mood disorders

ABSTRACT

Methods of treating mood disorders with compounds disclosed herein. Also provided are pharmaceutical compositions that include those compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International ApplicationNo. PCT/US2021/018534, filed Feb. 18, 2021, which claims the benefit of,and priority to, U.S. Provisional Application No. 62/978,075, filed onFeb. 18, 2020, the contents of each of which are incorporated herein byreference in their entirety.

BACKGROUND

Depression is a common psychological problem and refers to a mentalstate of low mood and aversion to activity. Various symptoms associatedwith depression include persistent anxious or sad feelings, feelings ofhelplessness, hopelessness, pessimism, and/or worthlessness, low energy,restlessness, irritability, fatigue, loss of interest in pleasurableactivities or hobbies, excessive sleeping, overeating, appetite loss,Insomnia, thoughts of suicide, and suicide attempts. The presence,severity, frequency, and duration of the above-mentioned symptoms varyon a case-by-case basis.

Approximately one third of patients with major depressive disorder (MDD)fail to achieve remission of their symptoms, even after multiple roundsof treatment with several known classes of antidepressants, includingselective serotonin reuptake inhibitors (SSRIs) (Rush et al. 2006). Thishigh prevalence of treatment-resistant depression (TRD) makes clear theneed for new, more efficacious pharmacotherapies for depression thatwill target new mechanisms and/or patient populations.

Tryptamines are monoamine alkaloids that contain an indole ring and arestructurally similar to the amino acid tryptophan, from which the namederives.

There are a significant number of tryptamine compounds that includenaturally occurring compounds and chemical derivatives with similarstructure that may be ring unsubstituted or ring substituted. Manytryptamines are 5HT_(2A) receptor agonists and/or modulators of otherserotonin receptors and are known to be psychoactive and, in many cases,cause prolonged hallucinations. The most well-known tryptamines arepsychedelic compounds, including compounds derived from entheogenicfungi (psilocybin and psilocin), N,N-dimethyltryptamine (DMT), lysergicacid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT),bufotenin, and ibogaine. These compounds are known to have significanteffects on thought, perception, and behavior. However, these compoundsare currently classified as Schedule I drugs under the ControlledSubstances Act due to their high abuse potential, no accepted medicaluse, and lack of established safety. Moreover, tryptamines aremetabolized by a number of pathways, in some cases including monoamineoxidase, limiting the oral bioavailability of some compounds andresulting in very short durations of action. Conversely, othertryptamines have very long durations of action, which makes themchallenging to use in a guided therapy setting, where supervisedsessions of many hours in duration are costly for patients andinconvenient for healthcare providers.

Accordingly, there remains a need for safe and effective tryptaminecompounds that can reliably be used for the treatment of mood disorders.

SUMMARY

The present disclosure includes compound 2:

or a pharmaceutically acceptable salt thereof.

Additionally, the present disclosure includes pharmaceuticalcompositions of compound 2 and methods of using the same.

Additionally, the present disclosure includes methods of treating mooddisorders in a patient in need thereof, comprising administering aneffective amount of compound 2 or compound 4:

or a pharmaceutically acceptable salt thereof.

For example, provided herein are methods and compositions directed totreating a mood disorder by administering to a patient in need thereof apharmaceutical composition comprising an effective amount of compound 2or compound 4, or a pharmaceutically acceptable salt thereof. Inembodiments, the methods and compositions may treat mood disorders thatinclude depressive disorders, bipolar and related disorders,substance-related disorders. and/or anxiety disorders.

In embodiments, the methods and compositions may treat mood disordersthat include obsessive-compulsive and related disorders. In embodiments,the methods and compositions may treat mood disorders that includetrauma- and stressor-related disorders. In embodiments, the methods andcompositions may treat mood disorders that include feeding and eatingdisorders. In embodiments, the methods and compositions may treat mooddisorders that include neurocognitive disorders. In embodiments, themethods and compositions may treat mood disorders that includeneurodevelopmental disorders. In embodiments, the methods andcompositions may treat mood disorders that include personalitydisorders. In embodiments, the methods and compositions may treat mooddisorders that include sexual dysfunctions. In embodiments, the methodsand compositions may treat mood disorders that include gender dysphoria.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a graph of concentration versus time comparison forCompounds 4, 5, and 6 in rat brain after subcutaneous administration(dose 10 mg/kg). Values are expressed as mean +/− standard error of themean.

FIG. 2 depicts a bar graph of Blockade of the Head Twitch Response inMice. A one-way ANOVA revealed a significant main effect of treatment(F(7,32)=36.91, P<0.0001) on the total number of HTR counts. Dunnett'smultiple comparisons test was used to test if a group was significantlydifferent from vehicle. Only Cmp 4 alone was significantly differentfrom vehicle (P<0.0001). **** P<0.0001 vs. vehicle.

FIG. 3 depicts a bar graph of immobility time in the FST. A one-wayANOVA revealed a significant main effect of treatment (F(9,99)=12.42,P<0.0001) on the total time spent immobile in the FST. Dunnett'smultiple comparisons test was used to test if a group was significantlydifferent from vehicle. All treatments except for Compound 2 at 0.1mg/kg were significantly different from vehicle. * P<0.05, **** P<0.0001vs. vehicle.

FIG. 4 depicts a bar graph of immobility time in the FST. A one-wayANOVA revealed a significant main effect of treatment (F(5.54)=14.09,P<0.0001) on the total time spent immobile in the FST. Dunnett'smultiple comparisons test was used to test if a group was significantlydifferent from vehicle. ** P<0.01, **** P<0.0001 vs. vehicle.

FIG. 5 depicts a bar graph of swimming time in the FST. A one-way ANOVArevealed a significant main effect of treatment (F(9,99)=2.653,P=0.0090) on the total time spent swimming in the FST. Dunnett'smultiple comparisons test was used to test if a group was significantlydifferent from vehicle. * P<0.05, ** P<0.01 vs. vehicle.

FIG. 6 depicts a bar graph of results of the conditioned placepreference test. The effect of Compound 4 was not significantlydifferent from vehicle.

FIG. 7 depicts results of the open field locomotor activity assay. Atwo-way ANOVA revealed a significant main effect of time(F(17,765)=189.4, P<0.0001), a significant main effect of treatment(F(4,45)=16.84, P<0.0001), and a significant treatment x timeinteraction (F(68,765)=9.366, P<0.0001).

FIG. 8. depicts a bar graph of results of the marble burying test. Aone-way ANOVA revealed a significant main effect of treatment(F(5,53)=15.79, P<0.0001). Dunnett's multiple comparisons test was usedto test if a group was significantly different from vehicle. * P<0.05,** P<0.01, **** P<0.0001 vs. vehicle.

DETAILED DESCRIPTION

The present disclosure includes a compound according to Formula I:

or a pharmaceutically acceptable salt thereof,

wherein

R₁ is optionally substituted C₁-C₄ aliphatic;R₂ is optionally substituted C₁-C₄ aliphatic;R₂₆ is selected from the group consisting of hydrogen, halogen, —CN,—OH, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, OAc, —OPO(OH)₂ and NH₂.

In some embodiments, R₁ is selected from the group consisting of Me, Et,nPr, iPr, cyclopropyl, allyl, isobutyl, cyclopropylmethyl. In someembodiments, R₂ is selected from the group consisting of Me, Et, nPr,iPr, cyclopropyl, allyl, isobutyl, cyclopropylmethyl.

In some embodiments, R₂₆ is selected from the group consisting ofhydrogen, F, Cl, Br, I, CF₃, Me, CN, OMe, OH, OAc, and NH₂. In someembodiments, R₂₆ is selected from the group consisting of F, Cl, Br, I,CF₃, Me, CN, OMe, OH, OAc, and NH₂. In some embodiments, R₂₆ is halogen.In some embodiments, R₂₆ is fluoro. In some embodiments, R₂₆ is chloro.In some embodiments, R₂₆ is bromo. In some embodiments, R₂₆ is iodo.

In embodiments, the present disclosure includes a compound selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure includes a compound selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure includes a compound selected fromthe group consisting of:

or a pharmaceutically acceptable salt thereof.

Described herein are methods and compositions for treating a mooddisorder by administering to a patient in need thereof a compounddisclosed herein. Also provided are pharmaceutical compositions thatinclude a compound disclosed herein.

In embodiments, the methods and compositions may be used to treat a mooddisorder including depressive disorders, e.g., major depressivedisorder, persistent depressive disorder, postpartum depression,premenstrual dysphoric disorder, seasonal affective disorder, psychoticdepression, disruptive mood dysregulation disorder,substance/medication-induced depressive disorder, and depressivedisorder due to another medical condition.

In some embodiments, depression conditions include major depressivedisorder and dysthymic disorder. In some embodiments, depressionconditions develop under unique circumstances, including, but are notlimited to, psychotic depression, postpartum depression, seasonalaffective disorder (SAD), mood disorder, depressions caused by chronicmedical conditions such as cancer or chronic pain, chemotherapy, chronicstress, post traumatic stress disorders, and bipolar disorder (or manicdepressive disorder). In some embodiments, depression conditions thatare expected to be treated according to this aspect of the presentdisclosure include, but are not limited to, major depressive disorder,dysthymic disorder, psychotic depression, postpartum depression,premenstrual syndrome, premenstrual dysphoric disorder, seasonalaffective disorder (SAD), anxiety, mood disorder, depressions caused bychronic medical conditions such as cancer or chronic pain, chemotherapy,chronic stress, post traumatic stress disorders, and bipolar disorder(or manic depressive disorder).

Also provided herein are methods of treating refractory depression,e.g., patients suffering from a depressive disorder that does not,and/or has not, responded to adequate courses of at least one, or atleast two, other antidepressant compounds or therapeutics. For example,provided herein is a method of treating depression in a treatmentresistant patient, comprising a) optionally identifying the patient astreatment resistant and b) administering an effective dose of adisclosed compound. As used herein “depressive disorder” encompassesrefractory depression. In some embodiments, refractory depression occursin patients suffering from depression who are resistant to standardpharmacological treatments, including tricyclic antidepressants, MAOIs,SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs,as well non-pharmacological treatments such as psychotherapy,electroconvulsive therapy, vagus nerve stimulation and/or transcranialmagnetic stimulation. In some embodiments, a treatment resistant-patientmay be identified as one who fails to experience alleviation of one ormore symptoms of depression (e.g., persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism) despite undergoingone or more standard pharmacological or non-pharmacological treatment.In certain embodiments, a treatment-resistant patient is one who failsto experience alleviation of one or more symptoms of depression despiteundergoing treatment with two different antidepressant drugs. In otherembodiments, a treatment-resistant patient is one who fails toexperience alleviation of one or more symptoms of depression despiteundergoing treatment with four different antidepressant drugs. In someembodiments, a treatment-resistant patient may also be identified as onewho is unwilling or unable to tolerate the side effects of one or morestandard pharmacological or non-pharmacological treatment.

In some embodiments, symptoms associated with depression include, butare not limited to, persistent anxious or sad feelings, feelings ofhelplessness, hopelessness, pessimism, and/or worthlessness, low energy,restlessness, irritability, fatigue, loss of interest in pleasurableactivities or hobbies, excessive sleeping, overeating, appetite loss,insomnia, thoughts of suicide, or suicide attempts. In some embodiments,various symptoms associated with anxiety include fear, panic, heartpalpitations, shortness of breath, fatigue, nausea, and headaches amongothers. In addition, patients suffering from any form of depressionoften experience anxiety. It is expected that the methods of the presentcondition can be used to treat anxiety or any of the symptoms thereof.In some embodiments, presence, severity, frequency, and duration ofsymptoms of depression vary on a case to case basis.

In embodiments, the methods and compositions may be used to treat a mooddisorder including bipolar and related disorders, e.g., bipolar Idisorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorder, and bipolarand related disorder due to another medical condition.

In embodiments, the methods and compositions may be used to treat a mooddisorder including substance-related disorders, e.g., preventing asubstance use craving, diminishing a substance use craving, and/orfacilitating substance use cessation or withdrawal. Substance usedisorders involve abuse of psychoactive compounds such as alcohol,caffeine, cannabis, inhalants, opioids, sedatives, hypnotics,anxiolytics, stimulants, nicotine and tobacco. As used herein“substance” or “substances” are psychoactive compounds which can beaddictive such as alcohol, caffeine, cannabis, hallucinogens, inhalants,opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine andtobacco. For example, the methods and compositions may be used tofacilitate smoking cessation or cessation of opioid use.

In embodiments, the methods and compositions may be used to treat a mooddisorder including anxiety disorders, e.g., separation anxiety disorder,selective mutism, specific phobia, social anxiety disorder (socialphobia), panic disorder, panic attack, agoraphobia, generalized anxietydisorder, substance/medication-induced anxiety disorder, and anxietydisorder due to another medical condition.

In embodiments, the methods and compositions may be used to treat a mooddisorder including obsessive-compulsive and related disorders, e.g.,obsessive-compulsive disorder, body dysmorphic disorder, hoardingdisorder, trichotillomania (hair-pulling disorder), excoriation(skin-picking) disorder, substance/medication-inducedobsessive-compulsive and related disorder, and obsessive-compulsive andrelated disorder due to another medical condition.

In embodiments, the methods and compositions may be used to treat a mooddisorder including trauma- and stressor-related disorders, e.g.,reactive attachment disorder, disinhibited social engagement disorder,posttraumatic stress disorder, acute stress disorder, and adjustmentdisorders.

In embodiments, the methods and compositions may be used to treat a mooddisorder including feeding and eating disorders, e.g., anorexia nervosa,bulimia nervosa, binge-eating disorder, pica, rumination disorder, andavoidant/restrictive food intake disorder.

In embodiments, the methods and compositions may be used to treat a mooddisorder including neurocognitive disorders, e.g., delirium, majorneurocognitive disorder, mild neurocognitive disorder, major or mildneurocognitive disorder due to Alzheimer's disease, major or mildfrontotemporal neurocognitive disorder, major or mild neurocognitivedisorder with Lewy bodies, major or mild vascular neurocognitivedisorder, major or mild neurocognitive disorder due to traumatic braininjury, substance/medication-induced major or mild neurocognitivedisorder, major or mild neurocognitive disorder due to HIV infection,major or mild neurocognitive disorder due to prion disease, major ormild neurocognitive disorder due to Parkinson's disease, major or mildneurocognitive disorder due to Huntington's disease, major or mildneurocognitive disorder due to another medical condition, and major ormild neurocognitive disorder due to multiple etiologies.

In embodiments, the methods and compositions may be used to treat a mooddisorder including neurodevelopmental disorders, e.g., autism spectrumdisorder, attention-deficit/hyperactivity disorder, stereotypic movementdisorder, tic disorders, Tourette's disorder, persistent (chronic) motoror vocal tic disorder, and provisional tic disorder. In someembodiments, a variety of other neurological conditions are expected tobe treated according to the methods of the present disclosure. In someembodiments, neurological conditions include, but are not limited to, alearning disorder, autistic disorder, attention-deficit hyperactivitydisorder, Tourette's syndrome, phobia, post-traumatic stress disorder,dementia, AIDS dementia, Alzheimer's disease, Parkinson's disease,spasticity, myoclonus, muscle spasm, bipolar disorder, a substance abusedisorder, urinary incontinence, and schizophrenia.

In embodiments, the methods and compositions may be used to treat a mooddisorder including personality disorders, e.g., borderline personalitydisorder.

In embodiments, the methods and compositions may be used to treat a mooddisorder including sexual dysfunctions, e.g., delayed ejaculation,erectile disorder, female orgasmic disorder, female sexualinterest/arousal disorder, genito-pelvic pain/penetration disorder, malehypoactive sexual desire disorder, premature (early) ejaculation, andsubstance/medication-induced sexual dysfunction.

In embodiments, the methods and compositions may be used to treat a mooddisorder including gender dysphoria.

In embodiments provided are methods and compositions for treating a mooddisorder by administering to a subject in need thereof an effectiveamount of ethylpropyltryptamine (EPT; Compound 1) or a pharmaceuticallyacceptable salt thereof.

In other embodiments provided are methods and compositions for treatinga mood disorder by administering to a subject in need thereof aneffective amount of methylethyltryptamine (MET; Compound 2) or apharmaceutically acceptable salt thereof.

In other embodiments provided are methods and compositions for treatinga mood disorder by administering to a subject in need thereof aneffective amount of a compound disclosed herein selected from thefollowing structures:

or a pharmaceutically acceptable salt thereof.

In other embodiments provided are methods and compositions for treatinga mood disorder by administering to a subject in need thereof aneffective amount of a compound disclosed herein selected from thefollowing structures:

or a pharmaceutically acceptable salt thereof.

In other embodiments provided are methods and compositions for treatinga mood disorder by administering to a subject in need thereof aneffective amount of a compound disclosed herein selected from thefollowing structures:

or a pharmaceutically acceptable salt thereof.

In other embodiments, provided herein are methods and compositions fortreating migraine, cluster headache, or other headache disorders byadministering to a patient in need thereof a compound of the presentdisclosure.

In other embodiments, provided herein are methods and compositions fortreating inflammation by administering to a patient in need thereof acompound of the present disclosure.

In embodiments, methods include treating a mood disorder, e.g., adepressive disorder, by administering to a patient in need thereof apharmaceutical composition including about 0.01 mg to about 400 mg of acompound disclosed herein. In embodiments, doses may be, e.g., in therange of about 0.01 to 400 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg,0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.1 mg, 0.1 to 300 mg, 0.1 to250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to5 mg, 0.1 to 1 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 300 mg,20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100to 300 mg, 100 to 250 mg, 100 to 200 mg, with doses of, e.g., about 0.25mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30, mg, 35mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg, 300 mg, and 400 mg being examples.

In specific embodiments, dosages may include amounts of a compounddisclosed herein in the range of about, e.g., 1 mg to 200 mg, 1 mg to100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mgto 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2mg to 10 mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg,6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80mg, 90 mg, 100 mg, 125 mg, 150 mg, and 200 mg being specific examples ofdoses.

Typically, dosages of a compound disclosed herein are administered once,twice, three or four times daily, every other day, every three days,once weekly, twice monthly, once monthly, or 3-4 times yearly to apatient in need thereof. In embodiments, the dosage is about, e.g.,1-400 mg/day, or 1-300 mg/day, or 1-250 mg/day, or 1-200 mg/day, forexample 300 mg/day, 250 mg/day, 200 mg/day, 150 mg/day, 100 mg/day, 75mg/day, 50 mg/day, 40 mg/day, 30 mg/day, 25 mg/day, 20 mg/day, 15mg/day, 10 mg/day, 5 mg/day, or 1 mg/day.

In embodiments, pharmaceutical compositions for parenteraladministration or inhalation, e.g., a spray or mist, of a compounddisclosed herein include a concentration of about 0.005 mg/ml to about500 mg/mL. In embodiments, the compositions include a compound disclosedherein at a concentration of, e.g., about 0.05 mg/mL to about 50 mg/mL,about 0.05 mg/mL to about 100 mg/mL, about 0.005 mg/mL to about 500mg/mL, about 0.1 mg/mL to about 50 mg/mL, about 0.1 mg/mL to about 10mg/mL, about 0.05 mg/mL to about 25 mg/mL, about 0.05 mg/mL to about 10mg/mL, about 0.05 mg/mL to about 5 mg/mL, or about 0.05 mg/mL to about 1mg/mL.

In embodiments, the composition includes a compound disclosed herein ata concentration of, e.g., about 0.05 mg/mL to about 15 mg/mL, about 0.5mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 5 mg/mL, about 0.5mg/mL to about 7 mg/mL, about 1 mg/mL to about 10 mg/mL, about 5 mg/mLto about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mL to 25mg/mL, about 5 mg/mL to 50 mg/mL, or about 10 mg/mL to 100 mg/mL. Inembodiments, the pharmaceutical compositions are formulated as a totalvolume of about, e.g., 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250mL, or 500 mL.

Typically, dosages may be administered to a subject once, twice, threeor four times daily, every other day, every three days, once weekly,twice monthly, once monthly, or 3-4 times yearly. In embodiments, acompound disclosed herein is administered to a subject once in themorning, or once in the evening. In embodiments, a compound disclosedherein is administered to a subject once in the morning, and once in theevening. In embodiments, a compound disclosed herein is administered toa subject three times a day (e.g., at breakfast, lunch, and dinner), ata dose, e.g., of 50 mg/administration (e.g., 150 mg/day).

In embodiments, a compound disclosed herein is administered to a subject12.5 mg/day in one or more doses. In embodiments, a compound disclosedherein is administered to a subject 25 mg/day in one or more doses. Inembodiments, a compound disclosed herein is administered to a subject 35mg/day in one or more doses. In embodiments, a compound disclosed hereinis administered to a subject 50 mg/day in one or more doses. Inembodiments, a compound disclosed herein is administered to a subject 75mg/day in one or more doses. In embodiments, a compound disclosed hereinis administered to a subject 100 mg/day in one or more doses. Inembodiments, a compound disclosed herein is administered to a subject150 mg/day in one or more doses. In embodiments, a compound disclosedherein is administered to a subject 200 mg/day in one or more doses. Inembodiments, a compound disclosed herein is administered to a subject250 mg/day in one or more doses.

In embodiments, the dosage of a compound disclosed herein is 0.0005-5mg/kg, 0.001-1 mg/kg, 0.01-1 mg/kg or 0.1-5 mg/kg once, twice, threetimes or four times daily. For example, in embodiments, the dosage is0.0005 mg/kg, 0.001 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.025 mg/kg, 0.05mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 2.5 mg/kg, or 5 mg/kg, once,twice, three times or four times daily. In embodiments, a subject isadministered a total daily dose of 0.01 mg to 500 mg of a compounddisclosed herein once, twice, three times, or four times daily. Inembodiments, the total amount administered to a subject in a 24-hourperiod is, e.g., 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg,0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300mg, 400 mg, or 500 mg. In embodiments, the subject may be started at alow dose and the dosage is escalated. In embodiments, the subject may bestarted at a high dose and the dosage is decreased.

In embodiments, a compound disclosed herein may be administered, e.g.,via inhalation or orally, at specified intervals. For example, duringtreatment a patient may be administered a compound disclosed herein atintervals of every, e.g., 1 year, 6 months, 90 days, 60 days, 30 days,14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours,4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours,1.25 hours, 1 hour, 0.75 hour, 0.5 hour, or 0.25 hour.

In embodiments, a compound of the present disclosure or apharmaceutically acceptable salt thereof is administered to a patientunder the supervision of a healthcare provider.

In embodiments, a compound of the present disclosure or apharmaceutically acceptable salt thereof is administered to a patientunder the supervision of a healthcare provider at a clinic specializingin the delivery of psychoactive treatments.

In embodiments, a compound of the present disclosure is administered toa patient under the supervision of a healthcare provider at a high doseintended to induce a psychedelic experience in the subject, e.g., 12.5mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, or 150 mg.

In some embodiments, the administration to a patient of a high doseunder the supervision of a healthcare provider occurs periodically inorder to maintain a therapeutic effect in the patient, e.g., every threedays, twice weekly, once weekly, twice monthly, once monthly, thriceyearly, twice yearly, or once yearly.

In some embodiments, a compound of the present disclosure or apharmaceutically acceptable salt thereof is administered by a patient ontheir own at home or otherwise away from the supervision of a healthcareprovider.

In some embodiments, a compound of the present disclosure or apharmaceutically acceptable salt thereof is administered by a patient ontheir own at home or otherwise away from the supervision of a healthcareprovider at a low dose intended to be sub-perceptual or to inducethreshold psychoactive effects, e.g., 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg,1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, or 10 mg.

In some embodiments, the administration by a patient of a low dose ontheir own occurs periodically in order to maintain a therapeutic effectin the patient, e.g., daily, every other day, every three days, twiceweekly, once weekly, twice monthly, or once monthly.

Suitable dosage forms for a compound disclosed herein include, but arenot limited to, oral forms, such as tablets, hard or soft gelatincapsules, powders, granules and oral solutions, syrups or suspensions,troches, as well as sublingual, buccal, intratracheal, intraocular, orintranasal forms, forms adapted to inhalation, topical forms,transdermal forms, or parenteral forms, for example, forms adapted forintravenous, intra-arterial, intraperitoneal, intrathecal,intraventricular, intramuscular or subcutaneous administration. Inembodiments, for such parenteral administration, it may be in the formof a sterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

Pharmaceutical compositions herein may be provided with immediaterelease, delayed release, extended release, or modified releaseprofiles. In embodiments, pharmaceutical compositions with differentdrug release profiles may be combined to create a two-phase orthree-phase release profile. For example, pharmaceutical compositionsmay be provided with an immediate release and an extended releaseprofile. In embodiments, pharmaceutical compositions may be providedwith an extended release and delayed release profile. Such compositionmay be provided as pulsatile formulations, multilayer tablets, orcapsules containing tablets, beads, granules, etc. Compositions may beprepared using a pharmaceutically acceptable “carrier” composed ofmaterials that are considered safe and effective. The “carrier” includesall components present in the pharmaceutical formulation other than theactive ingredient or ingredients. The term “carrier” includes, but isnot limited to, diluents, binders, lubricants, glidants, disintegrants,fillers, and coating compositions.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration or administration via an implant. Thecompositions may be prepared by any method well known in the art ofpharmacy.

Such methods include the step of bringing in association compounds usedin the disclosure or combinations thereof with any auxiliary agent. Theauxiliary agent(s), also named accessory ingredient(s), include thoseconventional in the art, such as carriers, fillers, binders, diluents,disintegrants, lubricants, colorants, flavoring agents, anti-oxidants,and wetting agents. Such auxiliary agents are suitably selected withrespect to the intended form and route of administration and asconsistent with conventional pharmaceutical practices.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets, dragées orcapsules, or as a powder or granules, or as a solution or suspension.The active ingredient may also be presented as a bolus or paste. Thecompositions can further be processed into a suppository or enema forrectal administration.

Tablets may contain the active ingredient compounds and suitablebinders, lubricants, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Gelatin capsules maycontain the active ingredient compounds and powdered carriers, such aslactose, starch, cellulose derivatives, magnesium stearate, stearicacid, and the like. Similar diluents can be used to make compressedtablets. Compressed tablets can be sugar coated or film coated to maskany unpleasant taste and protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

For oral administration in liquid dosage form, the oral drug componentsare combined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Examples ofsuitable liquid dosage forms include, but are not limited to, solutionsor suspensions in water, pharmaceutically acceptable fats and oils,alcohols or other organic solvents, including esters, emulsions, syrupsor elixirs, suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Such liquid dosage forms may contain, forexample, suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, thickeners, and melting agents.Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile solutions. In general, water, a suitable oil,saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water-soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.The compositions may be presented in unit-dose or multi-dose containers,for example sealed vials and ampoules, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition ofsterile liquid carrier, for example water, prior to use. For transdermaladministration, e.g. gels, patches or sprays can be contemplated.Compositions or formulations suitable for pulmonary administration e.g.by nasal inhalation, include fine dusts or mists which may be generatedby means of metered dose pressurized aerosols, nebulizers orinsufflators. Parenteral and intravenous forms may also include mineralsand other materials to make them compatible with the type of injectionor delivery system chosen.

The compounds used in the method of the present disclosure may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines. The compounds maybe administered as components of tissue-targeted emulsions.

The compounds used in the method of the present disclosure may also becoupled to soluble polymers as targetable drug carriers or as prodrugs.Such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical compositions herein may be provided with immediaterelease, delayed release, extended release, or modified releaseprofiles. In some embodiments, pharmaceutical compositions withdifferent drug release profiles may be combined to create a two-phase orthree-phase release profile. For example, pharmaceutical compositionsmay be provided with an immediate release and an extended-releaseprofile. In some embodiments, pharmaceutical compositions may beprovided with an extended release and delayed release profile. Suchcomposition may be provided as pulsatile formulations, multilayertablets, or capsules containing tablets, beads, granules, etc.

Pharmaceutical compositions herein may be provided with abuse deterrentfeatures by techniques know in the art, for example, by making a tabletthat is difficult to crush or to dissolve in water.

The disclosure further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material,including instructions for the use of the composition for a use ashereinbefore described.

The exact dose and regimen of administration of the composition willnecessarily be dependent upon the type and magnitude of the therapeuticor nutritional effect to be achieved and may vary depending on factorssuch as the particular compound, formula, route of administration, orage and condition of the individual subject to whom the composition isto be administered.

The compounds used in the method of the present disclosure may beadministered in various forms, including those detailed herein. Thetreatment with the compound may be a component of a combination therapyor an adjunct therapy, i.e. the subject or patient in need of the drugis treated or given another drug for the disease in conjunction with oneor more of the instant compounds. This combination therapy can besequential therapy where the patient is treated first with one drug andthen the other or the two drugs are given simultaneously. These can beadministered independently by the same route or by two or more differentroutes of administration depending on the dosage forms employed.

In some embodiments, compounds disclosed herein may be administered incombination with one or more other antidepressant treatments, such as,tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs for manufacturing a medicament fortreating depression, anxiety, and/or other related diseases, includingto provide relief from depression or anxiety and preventing recurrenceof depression or anxiety. In some embodiments, therapeutics that may beused in combination with a compound of the present disclosure include,but are not limited to, Anafranil, Adapin, Aventyl, Elavil, Norpramin,Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate,Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft,Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), andLudiomill.

Definitions

In the context of the present disclosure the term “5-HT2a receptoragonist” is intended to mean any compound or substance that activatesthe 5-HT2a receptor. The agonist may be a partial or full agonist.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “alkyl” refers to a straight or branched alkyl group. Exemplaryalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andtert-butyl.

The term “haloalkyl” refers to a straight or branched alkyl group thatis substituted with one or more halogen atoms.

The term “halogen” means F, Cl, Br, or I.

As used herein, the term “pharmaceutically acceptable” refers tomolecular entities and compositions that are “generally regarded assafe”, e.g., that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction when administered to ahuman. In embodiments, this term refers to molecular entities andcompositions approved by a regulatory agency of the federal or a stategovernment, as the GRAS list under sections 204(s) and 409 of theFederal Food, Drug and Cosmetic Act, that is subject to premarket reviewand approval by the FDA or similar lists, the U.S. Pharmacopeia oranother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R., —(haloR.), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR., —(CH₂)₀₋₂CH(OR.)₂; —O(haloR.), —CN, —N₃, —(CH₂)₀₋₂C(O)R.,—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR., —(CH₂)₀₋₂SR., —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR., —(CH₂)₀₋₂NR.₂, —NO₂, —SiR.₃, —OSiR.₃,—C(O)SR., —(C₁₋₄ straight or branched alkylene)C(O)OR., or —SSR. whereineach R. is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently selected from C₁₋₄aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R.,—(haloR.), —OH, —OR., —O(haloR.), —CN, —C(O)OH, —C(O)OR., —NH₂, —NHR.,—NR.₂, or —NO₂, wherein each R. is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and isindependently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R†, —NR†₂, —C(O)R†, —C(O)OR†, —C(O)C(O)R†,—C(O)CH₂C(O)R†, —S(O)₂R†, —S(O)₂NR†₂, —C(S)NR†₂, —C(NH)NR†₂, or—N(R†)S(O)₂R†; wherein each R† is independently hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, unsubstituted —OPh, or anunsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R†, taken together with their interveningatom(s) form an unsubstituted 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R† are independentlyhalogen, —R., —(haloR.), —OH, —OR., —O(haloR.), —CN, —C(O)OH, —C(O)OR.,—NH₂, —NHR., —NR.₂, or —NO₂, wherein each R. is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and isindependently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salts” includesboth acid and base addition salts, wherein the compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include but are not limited to mineral or organic acidsalts of basic residues such as amines, and alkali or organic salts ofacidic residues such as carboxylic acids. Pharmaceutically acceptablesalts include conventional non-toxic salts or quaternary ammonium saltsof the parent compound formed, for example, from non-toxic inorganic ororganic acids. Such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids; and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic,methanesulfonic, ethane disulfonic, and oxalic acids. Thepharmaceutically acceptable salts of a compound disclosed herein can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods.

The terms “about” or “approximately” as used herein mean within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, a range up to 10%, a range up to 5%, and/or arange up to 1% of a given value. Alternatively, particularly withrespect to biological systems or processes, the term can mean within anorder of magnitude, e.g., within 5-fold, or within 2-fold, of a value.“About” and “approximately” are used interchangeably herein.

In embodiments, the terms “effective amount” or “therapeuticallyeffective amount” refer to an amount of a compound, material,composition, medicament, or other material that is effective to achievea particular pharmacological and/or physiologic effect including but notlimited to reducing the frequency or severity of sadness or lethargy,depressed mood, anxious or sad feelings, diminished interest in all ornearly all activities, significant increased or decreased appetiteleading to weight gain or weight loss, insomnia, irritability, fatigue,feelings of worthlessness, feelings of helplessness, inability toconcentrate, and recurrent thoughts of death or suicide, or to provide adesired pharmacologic and/or physiologic effect, for example, reducing,inhibiting, or reversing one or more of the underlyingpathophysiological mechanisms underlying the neurological dysfunction,modulating dopamine levels or signaling, modulating serotonin levels orsignaling, modulating norepinephrine levels or signaling, modulatingglutamate or GABA levels or signaling, modulating synaptic connectivityor neurogenesis in certain brain regions, or a combination thereof. Theprecise dosage will vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system health, clinicalsymptoms etc.), the disease or disorder being treated, as well as theroute of administration and the pharmacokinetics of the agent beingadministered.

In embodiments, deuterium-enriched compounds disclosed herein and theiruse are contemplated and within the scope of the methods andcompositions described herein. Deuterium can be incorporated in anyposition in place of hydrogen (protium) synthetically, according tosynthetic procedures known in the art. For example, deuterium may beincorporated to various positions having an exchangeable proton, such asan amine N—H, via proton-deuterium equilibrium exchange. Thus, deuteriummay be incorporated selectively or non-selectively through methods knownin the art.

In some embodiments, the level of deuterium at each deuterium-enriched-H site of the compound is 0.02% to 100%.

In some embodiments, the level of deuterium at each deuterium-enriched—H site of the compound is 50%-100%, 70%-100%, 90%-100%, 95%-100%,96%-100%, 97%-100%, 98%-100%, or 99%-100%.

Exemplary deuterium-enriched compounds disclosed herein include:

The compounds disclosed herein may be racemic and/or optically activeisomers thereof. In this regard, some of the compounds can haveasymmetric carbon atoms, and therefore, can exist either as racemicmixtures or as individual optical isomers (enantiomers). Compoundsdescribed herein that contain a chiral center include all possiblestereoisomers of the compound, including compositions including theracemic mixture of the two enantiomers, as well as compositionsincluding each enantiomer individually, substantially free of the otherenantiomer. Thus, for example, contemplated herein is a compositionincluding the S enantiomer of a compound substantially free of the Renantiomer, or the R enantiomer substantially free of the S enantiomer.If the named compound includes more than one chiral center, the scope ofthe present disclosure also includes compositions including mixtures ofvarying proportions between the diastereomers, as well as compositionsincluding one or more diastereomers substantially free of one or more ofthe other diastereomers. By “substantially free” it is meant that thecomposition includes less than 25%, 15%, 10%, 8%, 5%, 3%, or less than1% of the minor enantiomer or diastereomer(s).Enumerated Embodiments

EXEMPLIFICATION

Methods for synthesizing, isolating, preparing, and administeringvarious stereoisomers are known in the art. Separation of diastereomersor cis and trans isomers may be achieved by conventional techniques,such as, for example, by fractional crystallization, chromatography orHigh-Performance Liquid Chromatography (HPLC) of a stereoisomericmixture of the agent or a suitable salt or derivative thereof. Anindividual enantiomer of a compound disclosed herein may also beprepared from a corresponding optically pure intermediate or byresolution, such as by HPLC of the corresponding racemate using asuitable chiral support or by fractional crystallization of thediastereomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

The compounds used in the method of the present disclosure may beprepared by techniques well known in organic synthesis and familiar to apractitioner ordinarily skilled in the art. For example, the compoundsmay be prepared by the synthetic transformations shown below undergeneral procedures and further described in the specific examples thatfollow.

Abbreviations ACN: Acetonitrile DCM: Dichloromethane DIPEA:Diisopropylethylamine DMAc: Dimethylacetamide DMSO: DimethylsulfoxideDMT: N,N-dimethyltryptamine

HLM: human liver micro somesHPLC: High-performance liquid chromatographyLCMS: Liquid Chromatography-mass spectrometryMAO: monoamine oxidase5-MeO-DMT: 5-methoxy-N,N-dimethyltryptamineMLM: mouse liver microsomesNADPH: Nicotinamide adenine dinucleotide phosphate hydrideNMR: Nuclear magnetic resonancePBS: phosphate buffered salinePd/C: Palladium on carbonRLM: rat liver microsomesR.T.: Room temperature/ambient temperature

THF: Tetrahydrofuran General Procedures

However, these may not be the only means by which to synthesize orobtain the desired compounds.

The present disclosure provides a pharmaceutical composition comprisingthe compound of the present disclosure and a pharmaceutically acceptablecarrier.

The subject disclosure is also intended to include all isotopes of atomsoccurring in the compounds disclosed herein. Isotopes include thoseatoms having the same atomic number but different mass numbers. By wayof general example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include ¹³C and ¹⁴C.

It will be noted that any notation of a carbon in structures throughoutthis application, when used without further notation, is intended torepresent all isotopes of carbon, such as ¹²C, ¹³C, or ¹⁴C. Furthermore,any compounds containing ¹³C or ¹⁴C may specifically have the structureof any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structuresthroughout this application, when used without further notation, isintended to represent all isotopes of hydrogen, such as ¹H, ²H, or ³H.Furthermore, any compounds containing ²H or ³H may specifically have thestructure of any of the compounds disclosed herein.

Isotopically-labeled compounds can generally be prepared by conventionaltechniques known to those skilled in the art using appropriateisotopically-labeled reagents in place of the non-labeled reagentsemployed.

It should be understood that the examples and embodiments providedherein are exemplary. Those skilled in the art will envision variousmodifications of the examples and embodiments that are consistent withthe scope of the disclosure herein. Such modifications are intended tobe encompassed by the claims.

EXAMPLES Example 1. Preparation of Compound 3

Step 1: Preparation of 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride

To a mixture of 5-fluoro-1H-indole (3 g, 22.20 mmol, 1 eq) in THF (30mL) was added oxalyl chloride (4.23 g, 33.30 mmol, 2.91 mL, 1.5 eq) inone portion at 0° C. under N₂. The mixture was stirred at 15° C. for 2hours. On completion, the reaction mixture was concentrated to obtain2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a yellow solid (5.01g, 22.21 mmol, 100% yield).

Step 2: Preparation ofN-ethyl-2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide

To a solution of N-ethylpropan-1-amine (2.90 g, 33.32 mmol, 4.63 mL, 1.5eq) in DCM (20 mL) was added N,N-diisopropylethylamine (5.74 g, 44.42mmol, 7.74 mL, 2 eq). Then 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetylchloride (5.01 g, 22.21 mmol, 1 eq) in THF (30 mL) was added at 0° C.Then the mixture was stirred at 15° C. for 2 hours. On completion, aq.NH₄Cl (30 mL) was added and the mixture was stirred for 5 min. Theaqueous phase was extracted with DCM (50 mL×3). The combined organicphase was dried with anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=5/1 to 0/1) to obtainN-ethyl-2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide as a whitesolid (5.28 g, 19.11 mmol, 86% yield). ¹H NMR (400 MHz, CDCl₃) (partialintegrals due to conformers) δ10.80 (br s, 1H), 7.94 (dd, J=2.0, 9.3 Hz,1H), 7.53 (d, J=3.2 Hz, 1H), 7.17 (ddd, J=1.2, 4.3, 8.9 Hz, 1H), 6.93(dt, J=2.4, 9.0 Hz, 1H), 3.58-3.49 (m, 1H), 3.48-3.39 (m, 1H), 3.35 (q,J=7.2 Hz, 1H), 3.29-3.20 (m, 1H), 1.76-1.53 (m, 2H), 1.25 (t, J=7.2 Hz,1.5H), 1.17 (t, J=7.2 Hz, 1.5H), 1.00 (t, J=7.6 Hz, 1.5H), 0.80 (t,J=7.2 Hz, 1.5H).

Step 3: Preparation ofN-ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-1 -amine hydrochloride(3)

To a solution ofN-ethyl-2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide (2 g, 7.24mmol, 1 eq) in THF (30 mL) was added lithium aluminum hydride (824.18mg, 21.72 mmol, 3 eq) at 0° C. The mixture was then stirred at 60° C.for 5 hours. On completion, the mixture was cooled to 0° C. Water (0.83mL) was added and the reaction mixture was stirred for 5 min. Then 30%aq. NaOH (0.83 mL) was added and the mixture was stirred until thesolids were white and free flowing. The mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified byprep-HPLC (column=Phenomenex luna C18 (250*70 mm, 15 μm); mobilephase=water(0.05% HCl)-ACN, B%=10%-34%; R_(T)=22 min) to affordN-ethyl-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]propan-1-amine hydrochloride(3) as a white solid (845.6 mg, 2.97 mmol, 41% yield). ¹H NMR (400 MHz,DMSO-d6) δ11.13 (br s, 1H), 10.53 (br s, 1H), 7.48-7.30 (m, 3H), 6.94(dt, J=2.4, 9.2 Hz, 1H), 3.33-2.94 (m, 8H), 1.85-1.57 (m, 2H), 1.26 (t,J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d6) (extrapeaks due to C-F coupling) δ158.40, 156.10, 133.35, 127.51, 127.41,126.00, 113.04, 112.94, 110.07, 110.03, 109.96, 109.70, 103.69, 103.46,52.87, 52.06, 46.94, 19.87, 17.01, 11.45, 8.86; LCMS (R_(T)=1.709 min,MS calc.: 248.17, [M+H]⁺=249.1).

Example 2. Preparation of Compound 4

Step 1: Preparation of 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride

To a mixture of 5-fluoro-1H-indole (3 g, 22.20 mmol, 1 eq) in THF (30mL) was added oxalyl chloride (4.23 g, 33.30 mmol, 2.91 mL, 1.5 eq) inone portion at 0° C. under N₂. The mixture was stirred at 15° C. for 2hours. On completion, the reaction mixture was concentrated to obtain2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a yellow solid (5.01g, 22.21 mmol, 100% yield).

Step 2: Preparation ofN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide

To a solution of N-methylethanamine hydrochloride (3.18 g, 33.31 mmol,1.5 eq) in DCM (20 mL) was added N,N-diisopropylethylamine (11.48 g,88.83 mmol, 15.47 mL, 4 eq). The mixture was stirred at 15° C. for 30min. Then 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (5.01 g, 22.21mmol, 1 eq) in THF (30 mL) was added at 0° C. Then the mixture wasstirred at 15° C. for 2.5 hours. On completion, aq. NH₄Cl (50 mL) wasadded and the mixture was stirred for 5 min. The aqueous phase wasextracted with DCM (50 mL×3). The combined organic phase was dried withanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=15/1 to 0/1) to obtainN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a whitesolid (4.30 g, 17.32 mmol, 78% yield). ¹H NMR (400 MHz, CDCl₃) (partialintegrals due to conformers) δ10.83-10.66 (m, 1H), 7.94 (dd, J=1.6, 9.2Hz, 1H), 7.64-7.53 (m, 1H), 7.18 (dd, J=4.4, 8.9 Hz, 1H), 6.94 (dt,J=2.8, 9.0 Hz, 1H), 3.56 (q, J=7.2 Hz, 0.8H), 3.36 (q, J=7.2 Hz, 1.2H),3.05 (s, 1.8H), 3.01 (s, 1.2H), 1.24 (t, J=7.2 Hz, 1.2H), 1.19 (t, J=7.2Hz, 1.8H).

Step 3: Preparation ofN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine hydrochloride(4)

To a solution ofN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide (1.73 g, 6.97mmol, 1 eq) in THF (30 mL) was added lithium aluminum hydride (795.46mg, 20.96 mmol, 3 eq) at 0° C. The mixture was then stirred at 60° C.for 5 hours. On completion, the mixture was cooled to 0° C. Water (0.8mL) was added and the mixture was stirred for 5 min. Then 30% aq. NaOH(0.8 mL) was added and the mixture was stirred until the solids werewhite and free flowing. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC(column=Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase=water(0.04%HCl)-ACN, B%=10%-30%; R_(T)=20 min) to affordN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine hydrochloride(4) as a white solid (670 mg, 2.61 mmol, 37% yield). ¹H NMR (400 MHz,DMSO-d6) δ11.11 (br s, 1H), 10.46 (br s, 1H), 7.48-7.30 (m, 3H), 6.93(dt, J=2.4, 9.2 Hz, 1H), 3.36-3.00 (m, 6H), 2.79 (d, J=5.2 Hz, 3H), 1.25(t, J=7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d6) (extra peaks due to C-Fcoupling) δ158.39, 156.09, 133.38, 127.49, 127.39, 125.96, 113.04,112.94, 109.98, 109.94, 109.72, 103.74, 103.51, 54.87, 50.38, 38.60,20.20, 9.32; LCMS (R_(T)=1.581 min, MS calc.: 220.14, [M+H]⁺=221.1).

Example 3. Preparation of Compound 5

Step 1: Preparation of 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride

To a solution of 5-fluoro-1H-indole (5 g, 37.00 mmol, 1 eq) in THF (50mL) was added oxalyl chloride (7.04 g, 55.50 mmol, 4.86 mL, 1.5 eq) at0° C. The mixture was stirred at 15° C. for 2 hours. On completion, thereaction mixture was concentrated to obtain2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (8.35 g, 37.01 mmol,100% yield) as yellow solid.

Step 2: Preparation of2-(5-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

To a solution of N-methylmethanamine hydrochloride (4.53 g, 55.52 mmol,5.09 mL, 1.5 eq) in DCM (50 mL) was added N,N-diisopropylethylamine(19.13 g, 148.05 mmol, 25.79 mL, 4 eq). The mixture was stirred at 15°C. for 0.5 h. Then a solution of 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetylchloride (8.35 g, 37.01 mmol, 1 eq) in THF (70 mL) was added at 0° C.and the mixture was stirred at 15° C. for 2 h. On completion, aq. NH₄Cl(100 mL) was added and the mixture was stirred for 5 min. The aqueousphase was extracted with DCM (60 mL×3) and the combined organic phasewas dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=5/1 to 0/1) to obtain2-(5-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide as a yellow solid(6.67 g, 28.48 mmol, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ10.33 (br s,1H), 7.96 (dd, J=2.0, 9.2 Hz, 1H), 7.69 (br d, J=1.6 Hz, 1H), 7.23 (dd,J=4.4, 8.8 Hz, 1H), 6.97 (dt, J=2.4, 9.0 Hz, 1H), 3.10 (s, 3H), 3.06 (s,3H).

Step 3: Preparation of2-(5-fluoro-1H-indol-3-yl)-N,N-dimethylethan-1-amine hydrochloride (5)

To a solution of 2-(5-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(2 g, 8.54 mmol, 1 eq) in THF (30 mL) was added lithium aluminum hydride(972.25 mg, 25.62 mmol, 3 eq) at 0° C. The mixture was then stirred at60° C. for 5 h. On completion, the mixture was cooled to 0° C. Water (1mL) was added and the mixture was stirred for 5 min. Then 30% aq. NaOH(1 mL) was added and the mixture was stirred until the solids were whiteand free flowing. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC (column=Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase=water(0.04%HCl)-ACN, B%=1%-27%; R_(T)=20 min) to afford2-(5-fluoro-1H-indol-3-yl)-N,N-dimethylethan-1-amine hydrochloride (5)as a white solid (1.22 g, 5.91 mmol, 69% yield). ¹H NMR (400 MHz,DMSO-d6) δ11.12 (br s, 1H), 10.47 (br s, 1H), 7.43 (dd, J=2.4, 10.1 Hz,1H), 7.39-7.30 (m, 2H), 6.93 (dt, J=2.4, 9.2 Hz, 1H), 3.32-3.22 (m, 2H),3.14-3.05 (m, 2H), 2.81 (d, J=4.4 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d6)(extra peaks due to C-F coupling) δ158.39, 156.09, 133.40, 127.47,127.38, 125.95, 113.05, 112.95, 109.98, 109.79, 109.73, 103.76, 103.53,56.95, 42.44, 20.56; LCMS (R_(T)=2.559 min, MS cal.: 206.12,[M+H]⁺=207.1).

Example 4. Metabolic Stability in Human Liver Microsomes

Disclosed compounds were tested for stability in human liver microsomes(HLM), with the results summarized in Table 1. Compound 2 exhibitedgreater metabolic stability than Compound 1, N,N-dimethyltryptamine(DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and psilocin inthis model. Compound 4 exhibited metabolic stability greater than itsdimethyl analog Compound 5 and ethylpropyl analog Compound 3, and lessthan its 4-hydroxy analog Compound 6.

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

HLM Stability. Pooled HLM from adult male and female donors (Corning452117) were used. Microsomal incubations were carried out in multi-wellplates. Liver microsomal incubation medium consisted of PBS (100 mM, pH7.4), MgCl₂ (1 mM), and NADPH (1 mM), with 0.50 mg of liver microsomalprotein per mL. Control incubations were performed by replacing theNADPH-cofactor system with PBS. Test compounds (1 μM, final solventconcentration 1.0%) were incubated with microsomes at 37° C. withconstant shaking. Six time points over 60 minutes were analyzed, with 60μL aliquots of the reaction mixture being drawn at each time point. Thereaction aliquots were stopped by adding 180 μL of cold (4° C.)acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol asinternal standards (IS), followed by shaking for 10 minutes, and thenprotein sedimentation by centrifugation at 4000 rpm for 20 minutes at 4°C. Supernatant samples (80 μL) were diluted with water (240 μL) andanalyzed for parent compound remaining using a fit-for-purpose liquidchromatography-tandem mass spectrometry (LC-MS/MS) method.

Data Analysis. The elimination constant (k_(el)), half-life (t_(1/2)),and intrinsic clearance (CL_(int)) were determined in a plot of ln(AUC)versus time, using linear regression analysis.

TABLE 1 Intrinsic clearance (CL_(int)) and half-life (t_(1/2)) ofcompounds in the presence of HLM. Cl_(int) (μL/min/ Compound Structuremg) t_(1/2) (min) DMT

198.6 7.0 Psilocin

12.6 109.7 5-MeO- DMT

101.9 13.6  1*

64.3 21.7  2*

11.2 125.7 3

106.4 13.0 4

28.9 47.9 5

299.7 4.6 6

<9.6 >145 *Values are the average of two independent experiments.

Example 5. Metabolic Stability in Mouse Liver Microsomes

Disclosed compounds were tested for stability in mouse liver microsomes(MLM), with the results summarized in Table 2. Compound 2 exhibitedmetabolic stability greater than its dimethyl analog DMT and ethylpropylanalog Compound 1, and less than its 4-hydroxy analog psilocin in thismodel. Compound 4 exhibited metabolic stability greater than itsdimethyl analog Compound 5 and ethylpropyl analog Compound 3, and lessthan its 4-hydroxy analog Compound 6.

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

MLM Stability. Pooled MLM from CD-1 mice (BIOIVT M00501) were used.Microsomal incubations were carried out in multi-well plates. Livermicrosomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl₂ (1mM), and NADPH (1 mM), with 0.50 mg of liver microsomal protein per mL.Control incubations were performed by replacing the NADPH-cofactorsystem with PBS. Test compounds (1 μM, final solvent concentration 1.0%)were incubated with microsomes at 37° C. with constant shaking. Six timepoints over 60 minutes were analyzed, with 60 μL aliquots of thereaction mixture being drawn at each time point. The reaction aliquotswere stopped by adding 180 μL of cold (4° C.) acetonitrile containing200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standards(IS), followed by shaking for 10 minutes, and then protein sedimentationby centrifugation at 4000 rpm for 20 minutes at 4° C. Supernatantsamples (80 μL) were diluted with water (240 μL) and analyzed for parentcompound remaining using a fit-for-purpose liquid chromatography-tandemmass spectrometry (LC-MS/MS) method.

Data Analysis. The elimination constant (k_(el)), half-life (t_(1/2)),and intrinsic clearance (CL_(int)) were determined in a plot of ln(AUC)versus time, using linear regression analysis.

TABLE 2 Intrinsic clearance (CL_(int)) and half-life (t_(1/2)) ofcompounds in the presence of MLM. Cl_(int) (μL/min/ Compound Structuremg) t_(1/2) (min) DMT

20.1 69.1 Psilocin

10.9 126.7 5-MeO- DMT

28.4 48.8 1

231.3 6.0 2

13.6 102.0 3

249.9 5.5 4

29.1 47.6 5

50.8 27.3 6

<9.6 >145

Example 6. Metabolic Stability in Rat Liver Microsomes

Disclosed compounds were tested for stability in rat liver microsomes(RLM), with the results summarized in Table 3. Compounds bearing a4-hydroxy group showed low to moderate clearance in this model, whileall other compounds showed high clearance.

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

RLM Stability. Pooled RLM from adult male and female donors (XenotechR1000) were used. Microsomal incubations were carried out in multi-wellplates. Liver microsomal incubation medium consisted of PBS (100 mM, pH7.4), MgCl₂ (1 mM), and NADPH (1 mM), with 0.50 mg of liver microsomalprotein per mL. Control incubations were performed by replacing theNADPH-cofactor system with PBS. Test compounds (1 μM, final solventconcentration 1.0%) were incubated with microsomes at 37° C. withconstant shaking. Six time points over 60 minutes were analyzed, with 60μL aliquots of the reaction mixture being drawn at each time point. Thereaction aliquots were stopped by adding 180 μL of cold (4° C.)acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol asinternal standards (IS), followed by shaking for 10 minutes, and thenprotein sedimentation by centrifugation at 4000 rpm for 20 minutes at 4°C. Supernatant samples (80 μL) were diluted with water (240 μL) andanalyzed for parent compound remaining using a fit-for-purpose liquidchromatography-tandem mass spectrometry (LC-MS/MS) method.

Data Analysis. The elimination constant (k_(el)), half-life (t_(1/2)),and intrinsic clearance (CL_(int)) were determined in a plot of ln(AUC)versus time, using linear regression analysis.

TABLE 3 Intrinsic clearance (CL_(int)) and half-life (t_(1/2)) ofcompounds in the presence of RLM. Cl_(int) (μL/min/ Compound Structuremg) t_(1/2) (min) DMT

136.7 10.1 Psilocin

18.3 75.6 5-MeO- DMT

98.8 14.0 1

970.3 1.4 2

1561.0 0.9 3

428.2 3.2 4

229.1 6.1 5

150.7 9.2 6

27.7 50.1

Example 7. Pharmacokinetics in Mice

The pharmacokinetics of disclosed compounds were studied in the plasma(Table 4) and brains (Table 5) of mice after intravenous (IV),subcutaneous (SC), and oral (PO) dosing. Compounds 2 and 4 demonstratedmuch improved absolute oral bioavailability (F) compared to theethylpropyl analog Compound 1, consistent with the greater stability ofCompounds 2 and 4 in mouse liver microsomes (see Example 5 above).Despite this much improved oral exposure, the half-life of Compounds 2and 4 was relatively short. The half-life of Compound 4 was intermediatebetween its dimethyl analog Compound 5 and its 4-hydroxy analog Compound6. Further, Compound 4 showed much greater brain exposure than itsdimethyl analog Compound 5 after SC administration. Overall, thefindings indicate that Compounds 2 and 4 may serve as orally active andshort-acting therapeutic agents.

Animals. Male C57BL/6 mice, aged 8-12 weeks, were used in these studies.Four mice were housed in each cage. Temperature and humidity weremaintained at 22±3° C. and 30-70%, respectively, and illumination wascontrolled to give a 12 h light and 12 h dark cycle. Temperature andhumidity were recorded by an auto-controlled data logger system. Allanimals were provided laboratory rodent diet. Reverse osmosis watertreated with ultraviolet light was provided ad libitum. Animals wererandomly assigned to treatment groups.

Drugs. Compounds 4 and 5 were prepared as described above. All othercompounds were commercially obtained. Test compounds were used as thehydrogen fumarate (1 and 2) or hydrochloride (3, 4, and 5) salts andwere dissolved in a vehicle consisting of normal saline. They were thenadministered intravenously (IV) via the tail vein, subcutaneously (SC),or orally (PO) via gavage at a dose of 1 or 10 mg/kg (calculated basedon the free base) and at a volume of 5 mL/kg body weight.

Sample Collection and Bioanalysis. Blood samples (approximately 60 μL)were collected under light isoflurane anesthesia (Surgivet®) from theretro orbital plexus at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h (4 animalsper time point). Immediately after blood collection, plasma washarvested by centrifugation at 4,000 rpm for 10 min at 4° C. and sampleswere stored at −70±10° C. until bioanalysis. Following blood collection,animals were immediately sacrificed, the abdominal vena-cava was cutopen, and the whole body was perfused from the heart using 10 mL ofnormal saline, and brain samples were collected from all animals. Afterisolation, brain samples were rinsed three times in ice-cold normalsaline (for 5-10 seconds/rinse using ˜5-10 mL normal saline indisposable petri dish for each rinse) and dried on blotting paper. Brainsamples were homogenized using ice-cold phosphate-buffered saline (pH7.4). Total homogenate volume was three times the tissue weight. Allhomogenates were stored at −70±10° C. until bioanalysis. Forbioanalysis, 25 μL aliquots of plasma/brain study samples or spikedplasma/brain calibration standards were added to individual pre-labeledmicro-centrifuge tubes followed by 100 μL of an internal standardsolution (glipizide, 500 ng/mL in acetonitrile) except for blanks, where100 μL of acetonitrile was added. Samples were vortexed for 5 minutesand then centrifuged for 10 minutes at 4,000 rpm at 4° C. Followingcentrifugation, 100 μL of each clear supernatant was transferred to a 96well plate and analyzed with a fit-for-purpose LC-MS/MS method, withauthentic samples of each analyte used for calibration andidentification.

Data Analysis. Pharmacokinetic parameters were estimated using thenon-compartmental analysis tool of Phoenix® WinNonlin software (Ver8.0).

TABLE 4 Selected pharmacokinetic parameters of compounds in plasma ofC57BL/6 mice (10 mg/kg unless otherwise indicated). T_(max) C_(max)*AUC_(0-last) t_(1/2) Cl (mL/ F Compound Route (h) (ng/mL) (h*ng/mL) (h)min/kg) (%)** Psilocin oral 0.17 85.9 51.1 1.96 NC 64 (1 mg/kg) IV NA195 79.9 1.1 204 NA 1 oral 0.08 20.32 22.1 1.88 NC 2.6 IV NA 3,820.7844.34 1.9 197.39 NA 2 oral 0.25 102.32 238.21 1.37 NC 44 IV NA 962.59544.61 1.48 304.48 NA 4 oral 0.25 272.25 623.37 1.34 NC 35 IV NA2,913.74 1,793.37 0.86 92.85 NA SC 0.5 631.13 1,173.65 0.9 NC 65 4 SC0.08 83.25 57.47 0.45 NC 32 (1 mg/kg) 5 SC 0.25 362.63 246.62 0.27 NC NC5 SC 0.08 41.59 10.99 NC NC NC (1 mg/kg) 6 SC 0.08 1,158.93 1,411.6 1.1NC NC *For IV, C_(max) = C0 values back-extrapolated to t = 0; **Basedon plasma AUC_(0-last); NC = not calculated; NA = not applicable.

TABLE 5 Selected pharmacokinetic parameters of compounds in brains ofC57BL/6 mice (10 mg/kg unless otherwise indicated). Com- T_(max)C_(max)* AUC_(0-last) t_(1/2) Cl (mL/ F pound Route (h) (ng/g) (h*ng/g)(h) min/kg) (%)** Psilocin oral 0.17 211 399 2.91 NC 57 (1 IV NA 1197702 3.03 24.1 NA mg/kg) 1 oral 0.25 101.08 68.93 0.66 NC 1.4 IV NA15,380.61 4,754.52 1.73 NC NA 2 oral 0.5 956.73 1,988.41 7.52 NC 51 IVNA 6,250.81 3,923.27 1.54 NC NA 4 oral 0.25 1,396.19 3,835.86 1.32 NC 37IV NA 7,976.02 10,471.19 0.94 NC NA SC 1 3,505.16 6,672.16 0.82 NC 64 4SC 0.25 460.84 320.97 0.37 NC 31 (1 mg/kg) 5 SC 0.25 777.92 376.09 NC NCNC 5 SC 0.08 22.04 NC NC NC NC (1 mg/kg)^(#) 6 SC 0.5 2,924.86 3,549.181.07 NC NC *For IV, C_(max) = C0 values back-extrapolated to t = 0**Based on brain AUC_(0-last); ^(#)Concentrations only quantifiable at0.08 and 0.25 h so PK parameters not calculated; NC = not calculated; NA= not applicable.

Example 8. Pharmacokinetics in Rats

The pharmacokinetics of disclosed compounds were studied in the plasma(Table 6) and brains (Table 7) of rats after subcutaneous (SC) dosing.Compound 4 demonstrated an intermediate exposure and elimination rate inthe plasma and brain compared to its dimethyl analog Compound 5 and its4-hydroxy analog Compound 6 (FIG. 1), consistent with a favorableduration of action for therapeutic use intermediate between DMT-likecompounds (very short duration) and psilocin-like compounds (longduration). Compound 4 also demonstrated much higher exposure in brainthan its dimethyl analog Compound 5.

Animals. Male Sprague Dawley rats, aged 8-12 weeks, were used in thesestudies. Four rats were housed in each cage. Temperature and humiditywere maintained at 22±3° C. and 30-70%, respectively, and illuminationwas controlled to give a 12 h light and 12 h dark cycle. Temperature andhumidity were recorded by an auto-controlled data logger system. Allanimals were provided laboratory rodent diet and were fasted for 4 hpre-dose and 2 h post-dose. Reverse osmosis water treated withultraviolet light was provided ad libitum. Animals were randomlyassigned to treatment groups.

Drugs. Compounds 4 and 5 were prepared as described above. Compound 6was commercially obtained. Test compounds were used as the hydrogenfumarate (6) or hydrochloride (4 and 5) salts and were dissolved in avehicle consisting of normal saline. They were then administeredsubcutaneously (SC) at a dose of 1 or 10 mg/kg (calculated based on thefree base) and at a volume of 5 mL/kg body weight.

Sample Collection and Bioanalysis. Blood samples (approximately 120 μL)were collected under light isoflurane anesthesia (Surgivet®) from theretro orbital plexus at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h (4 animalsper time point). Immediately after blood collection, plasma washarvested by centrifugation at 4,000 rpm for 10 min at 4° C. and sampleswere stored at −70±10° C. until bioanalysis. Following blood collection,animals were immediately sacrificed, the abdominal vena-cava was cutopen, and the whole body was perfused from the heart using 10 mL ofnormal saline, and brain samples were collected from all animals. Afterisolation, brain samples were rinsed three times in ice-cold normalsaline (for 5-10 seconds/rinse using ˜5-10 mL normal saline indisposable petri dish for each rinse) and dried on blotting paper. Brainsamples were homogenized using ice-cold phosphate-buffered saline (pH7.4). Total homogenate volume was three times the tissue weight. Allhomogenates were stored at −70±10° C. until bioanalysis. Forbioanalysis, 25 μL aliquots of plasma/brain study samples or spikedplasma/brain calibration standards were added to individual pre-labeledmicro-centrifuge tubes followed by 100 μL of an internal standardsolution (glipizide, 500 ng/mL in acetonitrile) except for blanks, where100 μL of acetonitrile was added. Samples were vortexed for 5 minutesand then centrifuged for 10 minutes at 4,000 rpm at 4° C. Followingcentrifugation, 100 μL of each clear supernatant was transferred to a 96well plate and analyzed with a fit-for-purpose LC-MS/MS method, withauthentic samples of each analyte used for calibration andidentification.

Data Analysis. Pharmacokinetic parameters were estimated using thenon-compartmental analysis tool of Phoenix® WinNonlin software (Ver8.0).

TABLE 6 Selected pharmacokinetic parameters of compounds in plasma ofSprague Dawley rats (10 mg/kg unless otherwise indicated). T_(max)C_(max) AUC_(0-last) t_(1/2) Compound Route (h) (ng/mL) (h*ng/mL) (h) 4SC 1 237.27 498.69 NC 4 (1 mg/kg) SC 0.5 41.26 46.80 NC 5 SC 0.25 242.52266.26 0.55 6 SC 2 624.18 2,999.38 NC NC = not calculated

TABLE 7 Selected pharmacokinetic parameters of compounds in brains ofSprague Dawley rats (10 mg/kg unless otherwise indicated). T_(max)C_(max) AUC_(0-last) t_(1/2) Compound Route (h) (ng/g) (h*ng/g) (h) 4 SC1 2,478.8 4,710.96 0.52 4 (1 mg/kg) SC 0.25 187.99 197.70 0.39 5 SC 0.25274.69 93.99 0.39 6 SC 2 6,158.42 30,638.13 2.09

Example 9. CYP Inhibition in Human Liver Microsomes

Inhibition of five major cytochrome P450 (CYP) enzymes (1A2, 2C9, 2C19,2D6, and 3A4) by the disclosed compounds was determined in human livermicrosomes (HLM) by using LC-MS/MS to monitor the metabolic conversionof a cocktail of reference CYP substrates in the presence and absence ofthe test compounds (Table 8). For indicated compounds, a fixed testconcentration of 10 μM was used and inhibition expressed as apercentage. For the remainder, multiple concentrations were tested andan IC₅₀ was determined. The test compounds generally exhibited limitedinhibition of CYPs. At most of the CYPs tested, Compounds 2 and 4exhibited the least inhibition. In particular, Compounds 2 and 4 showedsubstantially less inhibition of CYP2D6 than their ethylpropyl analogsCompounds 1 and 3, respectively.

Test Compounds. Compounds 3 and 4 were prepared as described above. Allother compounds were commercially obtained.

HLM Incubations. Pooled HLM from adult male and female donors (Corning452117) were used. Microsomal incubations were carried out in multi-wellplates. Liver microsomal incubation aliquots contained 1) PBS (100 mM,pH 7.4), MgCl₂ (3.3 mM), and NADPH (1 mM); 2) liver microsomal protein(0.2 mg/mL); 3) the reference CYP substrates: phenacetin for CYP1A2 (10μM), diclofenac for CYP2C9 (5 μM), (S)-mephenytoin for CYP2C19 (30 μM),dextromethorphan for CYP2D6 (5 μM), and midazolam for CYP3A4 (2 μM); and4) test compounds (10 μM), control inhibitors (3 μM α-naphthoflavone forCYP1A2, 3 μM sulfaphenazole for CYP2C9, 1 μM (+)-N-3-benzylnirvanol for2C19, 3 μM quinidine for CYP2D6, or 3 μM ketoconazole for CYP3A4), orsolvent (for uninhibited condition). Incubations were carried out at 37°C. with constant shaking for 10 minutes. The reaction aliquots werestopped by adding 400 μL of cold (4° C.) acetonitrile containing 200ng/mL tolbutamide and 200 ng/mL labetalol as internal standards (IS),followed by protein sedimentation by centrifugation at 4,000 rpm for 20minutes at 4° C.

Sample Analysis. Supernatant samples (200 μL) were diluted with water(100 μL) and the reference metabolites of each reference CYP substratewere quantified using a fit-for-purpose liquid chromatography-tandemmass spectrometry (LC-MS/MS) method. Percent inhibition by testcompounds or control inhibitors was calculated by comparing themetabolite formation in the presence of the inhibitor compared to themetabolite formation in the absence of the inhibitor.

TABLE 8 IC₅₀ or % inhibition at 10 μM of indicated CYPs by testcompounds. Com- CYP % Inhibition at 10 μM or (IC₅₀, μM)^(#) pound 3A42D6 1A2 2C19 2C9 DMT 5.5 5.8 7.3 0.0 2.7 5-MeO- 0.0 4.4 4.0 0.0 1.0 DMTPsilocin 0.0 13.7  22.5  0.0 0.0 1* 2.0 58.6  37.1  2.3 0.1 2 0.0 (>50)11.5 (31.5) 0.5 (>50) 0.0 (>50) 0.0 (>50) 3 (>50)    (1.9) (8.4)(>50)    (>50)    4 (>50)    (>50)    (>50)    (>50)    (>50)    6(>50)    (48.5)  (>50)    (>50)    (>50)    ^(#)Values in parenthesesare IC₅₀s; all other values are % inhibition at 10 μM; *Values are theaverage of two independent experiments.

Example 10. Stability in the Presence of Monoamine Oxidases

Disclosed compounds were tested for stability in the presence ofmonoamine oxidase A and B (MAO-A and MAO-B) in human liver mitochondriapreparations, with the results summarized in Table 9. Disclosedcompounds, with the exception of Compound 5, exhibited good MAOstability in this model. Compounds bearing two methyl substituents onthe amine and lacking a 4-hydroxy substituent on the indole (DMT,5-MeO-DMT, and 5) were highly metabolized by MAO. In contrast, compoundswith bearing an ethyl and propyl substituent on the amine (1 and 3) or a4-hydroxy substituent on the indole (psilocin and 6) were highly stablein the MAO preparation. Compounds 2 and 4 were of intermediatestability, consistent with their intermediate half-life and exposure inPK studies (see Examples 7 and 8).

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

Liver Mitochondria Incubations. Human liver mitochondria (XenotechH0610.M) were used. Mitochondrial incubations were carried out inmulti-well plates. Liver mitochondrial incubation medium consisted ofPBS (100 mM, pH 7.4) with 0.30 mg of liver mitochondrial protein per mL.Test compounds (1 μM, final solvent concentration 1.0%) were incubatedwith liver mitochondrial protein at 37° C. with constant shaking (totalreaction volume 100 μL per well). Six time points over 60 minutes wereanalyzed. At each time point, reactions were stopped by adding 300 μL ofcold (4° C.) acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mLlabetalol as internal standards (IS), followed by shaking for 10minutes, and then protein sedimentation by centrifugation at 4000 rpmfor 20 minutes at 4° C. Supernatant samples (100 μL) were diluted with5% trichloroacetic acid in water (300 μL) and analyzed for parentcompound remaining using a fit-for-purpose liquid chromatography-tandemmass spectrometry (LC-MS/MS) method.

Data Analysis. The elimination constant (k_(el)), half-life (t_(1/2)),and intrinsic clearance (CL_(int)) were determined in a plot of ln(AUC)versus time, using linear regression analysis.

TABLE 9 Intrinsic clearance (CL_(int)), half-life (t_(1/2)), and percentremaining of compounds in the presence of monoamine oxidases (humanmitochondrial preparation). t_(1/2) CL_(int(MAO)) Remaining Compound(min) (μL/min/mg) (t = 60 min) DMT 17.1 134.9 8.9% Psilocin >145 <15.9112.1% 5-MeO-DMT 52.9 43.6 47.1% 1 >145 <15.9 95.1% 2 >145 <15.9 84.5%3 >145 <15.9 97.7% 4 >145 <15.9 75.0% 5 8.7 266 0.9% 6 >145 <15.9 112.3%

Example 11. Functional Activity at Serotonin Receptors

Disclosed compounds were tested for agonist activity at severalserotonin receptor subtypes (5-HT2A, 2-HT2B, 5-HT2C, and 5-HT1A) usingCa²⁺ flux functional assays, with the results summarized in Table 10.All compounds exhibited potent agonist activity at 5-HT2A, suggestive ofpotential hallucinogenic activity as well as possible therapeuticeffects. However, the signaling efficacy at 5-HT2A and the selectivityfor this target over other serotonin receptors varied dramatically witheven small changes to the chemical structure. For example, Compounds 1and 3 showed little selectivity for 5-HT2A over 5-HT2B, whereasCompounds 2 and 4 were highly selective for 5-HT2A relative to 5-HT2B.At the same time, Compound 1 was a highly efficacious agonist at 5-HT2A(E_(max)=85.2%), whereas Compound 2 was a low efficacy partial agonist(E_(max)=36.2%). Fluorination at the 5 position of the indole ring alsohad unpredictable effects. For example, Compounds 3 and 4 were bothsignificantly more potent at the 5-HT1A receptor than theirnon-fluorinated analogs Compounds 1 and 2, respectively. In the case ofCompound 3, fluorination also increased potency at 5-HT2A relative toCompound 1. In the case of Compound 4, fluorination had little effect onpotency at 5-HT2A, but dramatically increased the maximal efficacycompared to Compound 2, resulting in a high efficacy rather than partialagonist. Fluorination also decreased the maximal efficacy of signalingat 5-HT2B, as Compounds 3 and 4 induced lower maximal activation thatCompounds 1 and 2, respectively, at this receptor.

Test Compounds. Compounds 3 and 4 were prepared as described above. Allother compounds were commercially obtained.

Functional Assays at 5-HT2A, 5-HT2B, and 5-HT1A. Agonist activity at5-HT2A, 5-HT2B, and 5-HT1A receptors was determined using a FLIPR Ca²⁺flux assay at WuXi AppTec (Hong Kong) Limited according to theirstandard protocols. Briefly, stably transfected cells expressing thereceptor of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for5-HT1A) were grown and plated in a 384 well plate and incubated at 37°C. and 5% CO₂ overnight. A solution of 250 mM probenecid in 1 mL FLIPRassay buffer was prepared fresh. This was combined with a fluorescentdye (Fluo-4 Direct™) to make a final assay concentration of 2.5 mM.Compounds were diluted 1:3.16 for 10 points and 750 nL was added to a384 well compound plate using ECHO along with 30 μL assay buffer. Thefluorescent dye was then added to the assay plate along with assaybuffer to a final volume of 40 μL. The cell plate was incubated for 50min at 37° C. and 5% CO₂ and placed into the FLIPR Tetra along with thecompound plate. 10 μL of references and compounds were then transferredfrom the compound plate into the cell plate and the fluorescent signalwas read.

Functional Assays at 5-HT2C. Agonist activity at 5-HT2C was determinedusing a FLIPR Ca²⁺ flux assay at Eurofins DiscoverX (Fremont, Calif.)according to their standard protocols. Briefly, stably transfected cellsexpressing the human 5-HT2C receptor were grown and plated in a 384 wellplate and incubated at 37° C. and 5% CO₂ overnight. Assays wereperformed in 1× Dye Loading Buffer consisting of 1× Dye, 1× Additive A,and 2.5 mM Probenecid in HBSS/20 mM Hepes. Probenecid was preparedfresh. Cells were loaded with dye prior to testing and incubated at 37°C. for 30-60 minutes. After dye loading, cells were removed from theincubator and 10 μL HBSS/20 mM Hepes was added. 3× vehicle was includedin the assay buffer. Cells were incubated for 30 mins at roomtemperature in the dark to equilibrate plate temperature. Intermediatedilution of sample stocks was performed to generate 4× sample in assaybuffer. Compound agonist activity was measured on a FLIPR Tetra (MDS).Calcium mobilization was monitored for 2 minutes and 10 μL 4× sample inHBSS/20 mM Hepes was added to the cells 5 seconds into the assay.

TABLE 10 Agonist activity of compounds at select serotonin receptors inCa²⁺ flux functional assays. 5-HT2A 5-HT2B 5-HT2C 5-HT1A 5-HT2A % Act5-HT2B % Act 5-HT2C % Act 5-HT1A % Act EC₅₀ @ Max EC₅₀ @ Max EC₅₀ @ MaxEC₅₀ @ Max Compound (nM) Dose (nM) Dose (nM) Dose (nM) Dose 1 30.5 85.240.3 80.4 33.4 90.8 88,700 75.5 2 17.1 36.2 >100,000 22.5 28.3 89.759,500 73.6 3 5.535 104.1 15.42 64.64 NT NT 19,581 88.34 4 20.687.6 >10,000 0.79 9.459 85.13 16,918 83.01 6 15.14 103.0 >10,000 1.09 NTNT 14,709 72.96 DMT* 22.2 93.4 >31,600 10.4 31.3 92.0 >100,000 68.1psilocin* 6.50 95.6 4,290 1.44 30.3 95.1 >3,160 0.720 5-MeO- 1.76 10630.1 20.5 10.1 89.8 280 78.8 DMT* *Values are the average of two or moreindependent experiments; NT = not tested.

Example 12. Effects on the Head Twitch Response (HTR) in Mice

Disclosed compounds were tested for their ability to induce a headtwitch response (HTR) in mice, with the results summarized in Table 11.Consistent with their agonist activity at the 5-HT2A receptor, alltested compounds induced the HTR. However, the disclosed compoundsvaried in their maximal effect in this assay. The maximal effects offluorinated Compounds 3 (29.33 head twitches/20 min) and 4 (27.67 headtwitches/20 min) were both much higher than those of theirnon-fluorinated counterparts Compounds 1 (14.7 head twitches/20 min) and2 (6.00 head twitches/20 min), respectively, consistent with the higherefficacy of Compounds 3 and 4 as 5-HT2A agonists in vitro (see Example11 above). The maximal HTR induced by Compounds 3 and 4 was similar tothat of the prototype 5-HT2A agonist 4-iodo-2,5-dimethoxyamphetamine(DOI) (35.6 head twitches/20 min). Additionally, pretreatment with 0.1mg/kg (SC) of the selective 5-HT2A antagonist MDL100907 completelyblocked the HTR induced by Compound 4, even at very high doses (FIG. 2),demonstrating that the HTR induced by Compound 4 is dependent on 5-HT2Aactivation.

Animals. Adult male C57BL/6 mice, aged 8 weeks (body weight 20-25 g)were used in these experiments. Animals were housed under controlledtemperatures and 12-hour light/dark cycles (lights on between07:00-19:00 h), with ad libitum food and water. The protocol wasapproved by the Eurofins Advinus Institutional Animal Care and UseCommittee. This study was carried out in strict accordance with therecommendations in the Guide for the Care and Use of Laboratory Animalsof the National Institutes of Health. All efforts were made to minimizesuffering.

Drugs and Drug administration. Compounds 3 and 4 were prepared asdescribed above. All other compounds were commercially obtained. Testcompounds were used as the hydrogen fumarate (1 and 2) or hydrochloride(DOI, 3, and 4) salts. Drugs were dissolved in a vehicle consisting ofnormal saline and administered subcutaneously (SC) in a volume of 10mL/kg. Test compounds were administered at 5 doses per compound (0.1 to100 mg/kg, as indicated, calculated based on the free base) using N=6animals/group. The control compound DOI was administered at 1 dose (3.16mg/kg, calculated based on the HCl salt), using N=12 animals. Forblockade experiments, MDL100907 (0.1 mg/kg, SC) was administered 10 minsprior to the test compound.

Procedure. Mice were administered one dose of a test drug (or vehicle)s.c. and immediately placed into a small open field for behavioralobservation. Animals were observed continuously for 20 mins and thenumber of HTRs were counted by an observer blind to the treatmentcondition.

Statistical analysis. The data points shown in Table 11 are the mean ±standard error of the mean (SEM). Analysis was performed using GraphPadPrism 9.

TABLE 11 HTR of compounds in mice. Dose Average HTR Compound (mg/kg)(SEM) DOI 3.16 35.583 (3.372) 1 1 14.667 (2.848) 1 3.16 12.167 (1.682) 110 8.000 (1.966) 1 31.6 4.750 (1.797) 1 100 4.500 (0.866) 2 1 3.667(0.615) 2 3.16 6.000 (0.632) 2 10 2.500 (0.563) 2 31.6 1.000 (0.408) 2100 0.500 (0.500) 3 0.1 12.5 (0.671) 3 0.316 15.667 (1.33) 3 1 29.333(2.186) 3 3.16 22.167 (1.537) 3 10 26.333 (1.667) 4 0.1 5.00 (1.065) 40.316 14.00 (0.816) 4 1 18.333 (1.229) 4 3.16 27.667 (1.626) 4 10 9.333(1.022)

Example 13. Forced Swim Test in Rats

Disclosed compounds induced antidepressant-like effects in the forcedswim test (FST) in rats with a 23.5-h pre-treatment time. Specifically,the compounds reduced immobility time relative to vehicle control,indicative of an antidepressant-like effect (FIG. 3 and FIG. 4). Theseeffects on immobility were observed 23.5 hours after a single compoundadministration, a time point at which most or all of the drug has beencleared from the systemic circulation, suggesting that the compoundshave both rapid-acting and long-lasting antidepressant-like effects.Additionally, the compounds induced significant increases in swimmingbehavior during the test (FIG. 5). These effects on swimming werestronger than those induced by the control antidepressant desipramine.

Animals. Male Sprague Dawley rats, aged 8-10 weeks, were used in theexperiments. Animals were housed in groups of 2 under controlledtemperature (22±3° C.) and relative humidity (30-70%) conditions, with12-hour light/dark cycles, and with ad libitum food and water. Thesestudies were carried out in strict accordance with the requirements ofthe Committee for the Purpose of Control and Supervision of Experimentson Animals (CPCSEA), India. All efforts were made to minimize suffering.

Drugs and Drug Administration. Compound 4 was prepared as describedabove. All other compounds were commercially obtained. Test compounds,saline vehicle, and the positive control desipramine were administeredsubcutaneously (SC), with doses calculated based on the free base.Normal saline was used as the vehicle. All compounds were administeredat a volume of 5 mL/kg. Test compounds and vehicle were administered 0.5h after the start of the training swim (Swim 1) and 23.5 h before thetest swim (Swim 2). Desipramine was administered 3 times, at 23.5 h, 5h, and 1 h before the test swim (Swim 2), each time at a dose of 20mg/kg.

Forced Swim Test (FST). Animals were randomized based on body weight,and it was ensured that inter-group variations were minimal and did notexceed ±20% of the mean body weight across the groups. Group size wasN=10 per treatment, except for the vehicle and desipramine groups, whichwere N=20. Rats were handled for about 2 min daily for the 5 days priorto the beginning of the experimental procedure. On the first day of theexperiment (i.e., Day 0), post randomization, training swim sessions(Swim 1) were conducted between 12:00 and 18:00 h with all animals byplacing rats in individual glass cylinders (46 cm tall×20 cm indiameter) containing 23-25° C. water 30 cm deep for 15 minutes. At theconclusion of Swim 1, animals were dried with paper towels, placed inheated drying cages for 15 minutes, and then returned to their homecages. Animals were then administered the appropriate drug or vehicletreatment(s), as described above. For clarity, a compound administrationtime of 23.5 h before Swim 2 means 0.5 h after the start of Swim 1 and0.25 h after the completion of Swim 1 (i.e., immediately after return tothe home cage). On Day 1 (i.e., 24 h after start of Swim 1), animalsperformed the test swim (Swim 2) for a period of 5 min but otherwiseunder the same conditions as Swim 1. During all swim sessions, the waterwas changed between each animal.

Behavioral scoring was conducted by observers who were blind to thetreatment groups. Animals were continuously observed during Swim 2 andthe total time spent engaging in the following behaviors was recorded:immobile, swimming, and climbing. A rat was judged to be immobile whenit remained floating in the water without struggling and was making onlythose movements necessary to keep its head above water. A rat was judgedto be swimming when it made active swimming motions, more than necessaryto merely maintain its head above water (e.g., moving around in thecylinder). A rat was judged to be climbing when it made active movementswith its forepaws in and out of the water, usually directed against thewalls.

Statistical Analysis. The data points shown in FIG. 3, FIG. 4, and FIG.5 represent the mean ± standard error of the mean (SEM). Analysis wasperformed using GraphPad Prism 9. Comparisons between groups wereperformed using the one-way analysis of variance (ANOVA), followed byDunnett's test for comparisons to vehicle.

Example 14. Conditioned Place Preference in Mice

In the conditioned place preference model of abuse liability in mice,Compound 4 did not induce any significant preference for the drug-pairedcompartment (FIG. 6).

Animals. Male C57BL/6 mice, 5-8 weeks of age, (body weight 25-30 g;Envigo, Indianapolis, Ind., USA) were housed 5 per polycarbonate tubwith soft bedding in a temperature- and humidity-controlled vivarium.Mice were maintained under a 12-h light/dark cycle with lights on at06:00. Food and water were available ad libitum. Animals acclimated tothe vivarium for 1 week prior to experimental manipulations.

Drugs and Drug Administration. Compound 4 was prepared as describedabove. All other compounds were commercially obtained. Compound 4 andsaline vehicle were administered subcutaneously (SC), with dosescalculated based on the HCl salt, while the positive control oxycodonewas administered intraperitoneally (IP), with the dose calculated basedon the HCl salt. Normal saline was used as the vehicle. All compoundswere administered at a volume of 10 mL/kg. Compound 4, positive control,or vehicle were administered immediately before the start of eachconditioning session.

Conditioned Place Preference. Reward and/or aversion was assessed inconditioned place preference chambers (Model MED-CPP-3013; MedAssociates, St. Albans, Vt.). Each chamber (16.75×12.70 cm) has twostimulus-distinct conditioning chambers (wall color and flooringtexture) separated by a third central start chamber. Manual guillotinedoors permit confinement/access to individual chambers.

Group size was n=10 per treatment. Mice were habituated to the chambersfor 15 minutes. The following day, the mice were placed back into thechambers for 15 minutes to establish baselines preferences. Drugs werethen administered over a total of 6, 45-minute conditioning trialswhereby the test drug was paired to the compartment less preferred(based on baseline score) during 3 conditioning trials (S+) and thevehicle was paired to the preferred compartment (based on baselinescore) during 3 conditioning trials (S−). Final drug preference wasassessed in a 15-minute post-conditioning trial and was calculated bysubtracting the time in the drug-paired compartment at baseline from thetime in the drug-paired compartment post-conditioning, with positivevalues reflecting reward and negative values reflecting aversion.

For all trials, time spent in chambers as well as movement wasquantified by infrared photobeam detectors and calculated by Med-PC IVsoftware. Movement was defined as consecutive beam breaks within achamber to detect forward locomotion. The test apparatus was thoroughlycleaned with 70% ethanol solution after each trial.

Statistical Analysis. The data points shown are the mean ± standarderror of the mean (SEM). Analysis was performed using GraphPad Prism 9.Comparisons between groups were performed using the one-way analysis ofvariance (ANOVA), followed by Dunnett's test for comparisons to vehicle.

Example 15. Locomotor Activity in Mice

Compound 4 produced a dose-dependent decrease in total locomotoractivity in the open field, indicative of a sedative-like effect. Thehighest dose group showed a near complete reduction in activity (FIG.7).

Animals. Male C57BL/6 mice, 5-8 weeks of age, (body weight 25-30 g;Envigo, Indianapolis, Ind., USA) were housed 5 per polycarbonate tubwith soft bedding in a temperature- and humidity-controlled vivarium.Mice were maintained under a 12-h light/dark cycle with lights on at06:00. Food and water were available ad libitum. Animals acclimated tothe vivarium for 1 week prior to experimental manipulations.

Drugs and Drug Administration. Compound 4 was prepared as describedabove. Compound 4 and saline vehicle were administered subcutaneously(SC), with doses calculated based on the HCl salt. Normal saline wasused as the vehicle. All compounds were administered at a volume of 10mL/kg. Compound 4 or vehicle were administered immediately before thestart of the recording session.

Locomotor Activity. Locomotor activity was measured in experimentalcages (length×width×height: 560×560×330 mm) by an animal movementanalysis system SCANET MV-40 (MELQUEST Co., Ltd., Toyama, Japan). Thecumulative activity was recorded for 30 minutes prior to drugadministration to establish a baseline, and then animals were recordedfor 60 minutes immediately after drug administration. Cages were cleanedbetween testing sessions.

Statistical Analysis. The total number of beam breaks were summed into5-minute time bins. The data points shown are the mean ±standard errorof the mean (SEM). Analysis was performed using GraphPad Prism 9.Statistical analysis was performed using the two-way analysis ofvariance (ANOVA).

Example 16. Marble Burying in Mice

Compound 4 produced an anxiolytic-like effect in the marble burying test(MBT) in C57BL/6 mice (FIG. 8). Specifically, Compound 4 showed adose-dependent reduction in the number of marbles buried in a 30-minuteperiod compared to vehicle.

Animals. Adult male C57BL/6 mice, aged 8-10 weeks (body weight 20-25g),were used in these experiments. Animals were housed under controlledtemperatures and 12-hour light/dark cycles (lights on between07:00-19:00 h), with ad libitum food and water. All efforts were made tominimize suffering.

Drugs and Drug Administration. Compound 4 was prepared as describedabove. Desipramine HCl was commercially obtained. The test compound,vehicle, and the positive control desipramine were administeredsubcutaneously (SC), with doses calculated based on the freebase. Normalsaline was used as the vehicle. All compounds were administered at avolume of 10 mL/kg. All treatments were administered 30 minutes prior tothe start of behavioral testing. Group size was n=9-10 per treatment.

Marble Burying Test (MBT). Animals were randomized based on body weight,and it was ensured that inter-group variations were minimal and did notexceed ±20% of the mean body weight across the groups. Mice were handledfor about 2 min daily for the 3 days prior to the beginning of theexperimental procedure. Twenty glass marbles (16 mm diameter) wereplaced at equal distances in a 5×4 pattern on a 5-cm layer of corn-cobbedding, with marbles at least 2 cm from the borders of the cage. Thetotal number of marbles buried were counted in three 10-minute time bins(total 30 minutes). A marble was considered buried when it was >⅔covered by bedding material.

Statistical Analysis. The data points shown are the mean ± standarderror of the mean (SEM). Analysis was performed using GraphPad Prism 6.Comparisons between groups were performed using the one-way analysis ofvariance (ANOVA), followed by Dunnett's test for comparisons to vehicle.

Example 17. Stability in Mouse Brain Homogenate

Disclosed compounds were tested for stability in mouse brain homogenate(Table 12). There was variable stability among the test compounds underthe conditions of the experiment. Psilocin, 5-MeO-DMT, and Compounds 1and 3 demonstrated high stability, Compounds 2, 4, and 6 demonstratedintermediate stability, and DMT and Compound 5 were highly unstableunder the incubation conditions. Fluorinated Compounds 3 and 4 were lessstable than their non-fluorinated counterparts Compounds 1 and 2,respectively. Methylethyl Compounds 2 and 4 were more stable than theirdimethyl counterparts DMT and Compound 5, respectively.

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

Mouse Brain Homogenate Stability. Frozen mouse brain homogenate (pooledfrom male CD-1 mice, BioreclamationIVT, MSE00BRAINMZA) was thawed in awater bath at 37° C. immediately prior to use. Positive controls andtest compounds (final concentration in incubation medium=1 μM for testcompounds and 2 μM for controls, all with 2% DMSO) were incubated induplicate for each time point (0, 10, 30, 60, and 120 min) in the mousebrain homogenate at a total reaction volume of 100 μL at 37° C. At theend of each incubation period, reactions were immediately quenched with400 μL of acetonitrile containing internal standard (200 ng/mLtolbutamine and 200 ng/mL labetalol) and mixed thoroughly. Plates werethen sealed, shaken for 20 min, and centrifuged at 4,000 rpm and 4° C.for 20 min. Aliquots of 50 μL of each supernatant were diluted into 100uL of water and the mixtures were then shaken again for 10 min. Theresulting mixtures were analyzed for parent compound remaining using afit-for-purpose LC-MS/MS method.

TABLE 12 Stability of compounds in mouse brain homogenate. % CompoundRemaining t1/2 Compound (after 120 min) (min) DMT 0.0 6.4 5-MeO-DMT91.2 >289.1 psilocin 97.6 >289.1 1 113.8 >289.1 2 47.8 123 3 76.7 >289.14 20.7 54.3 5 0.0 3.1 6 16.7 45.8

Example 18. Stability in Rat Brain Homogenate

Disclosed compounds were tested for stability in rat brain homogenate(Table 13). There was variable stability among the test compounds underthe conditions of the experiment. Compounds 1, 2, and 3 demonstratedhigh stability, psilocin and Compounds 4 and 6 demonstrated intermediatestability, and DMT, 5-MeO-DMT, and Compound 5 were highly unstable underthe incubation conditions. Methylethyl Compounds 2 and 4 were morestable than their dimethyl counterparts DMT and Compound 5,respectively.

Test Compounds. Compounds 3, 4, and 5 were prepared as described above.All other compounds were commercially obtained.

Rat Brain Homogenate Stability. Frozen rat brain homogenate (pooled frommale Sprague Dawley rats, BioreclamationIVT, RAT00BRAINMZA) was thawedin a water bath at 37° C. immediately prior to use. Positive controlsand test compounds (final concentration in incubation medium=1 μM fortest compounds and 2 μM for controls, all with 2% DMSO) were incubatedin duplicate for each time point (0, 10, 30, 60, and 120 min) in the ratbrain homogenate at a total reaction volume of 100 μL at 37° C. At theend of each incubation period, reactions were immediately quenched with400 μL of acetonitrile containing internal standard (200 ng/mLtolbutamine and 200 ng/mL labetalol) and mixed thoroughly. Plates werethen sealed, shaken for 20 min, and centrifuged at 4,000 rpm and 4° C.for 20 min. Aliquots of 50 μL of each supernatant were diluted into 100uL of water and the mixtures were then shaken again for 10 min. Theresulting mixtures were analyzed for parent compound remaining using afit-for-purpose LC-MS/MS method.

TABLE 13 Stability of compounds in rat brain homogenate. % CompoundRemaining t_(1/2) Compound (after 120 min) (min) DMT 0.0 5.1 5-MeO-DMT0.3 14.4 Psilocin 46.1 114.8 1 86.9 >289.1 2 76.5 >289.1 3 103.3 >289.14 62.0 182.9 5 0.0 2.7 6 20.9 53.0

Example 19. Inhibition of Serotonin Transporter

The ability of disclosed compounds to inhibit uptake of monoamines bythe serotonin transporter (SERT) was measured using a fluorescentsubstrate uptake assay in transfected cells. Data are presented in Table14. Compounds were of variable potency for inhibition of SERT.Fluorinated Compound 4 was the most potent of the compounds tested atSERT and much more potent than its non-fluorinated counterpart Compound2 at this target.

Test Compounds. Compound 4 was prepared as described above. All othercompounds were commercially obtained.

SERT Uptake Inhibition. The ability of test compounds to block monoamineuptake by SERT was determined using the Neurotransmitter TransporterUptake Assay Kit manufactured by Molecular Devices (Cat #R8173).Briefly, stably transfected HEK293 cells expressing SERT were grown andplated into 384-well plates at a concentration of 20,000 cells per well.Plates were then incubated for 16-20 h at 37° C. and 5% CO₂. The mediumwas then aspirated and replaced with 25 μL of assay buffer (20 mM HEPESin HBSS, containing 0.1% BSA) containing the test compounds at theappropriate concentrations. Plates were then centrifuged at 300 rpm for15 s and then incubated at 37° C. for 30 minutes. At this time, 25 μL ofthe proprietary fluorescent dye solution was added, the plates wereincubated at 37° C. for 60 minutes, and then fluorescence was quantifiedon a plate reader (excitation wavelength=440 nm, emission wavelength=520nm). The proprietary dye solution contains a mixture of 1) a fluorescentdye (dye 1) that mimics the endogenous substrate of SERT and is therebyactively transported to the intracellular compartment in the absence ofan inhibitor and 2) a masking dye that inhibits the fluorescence of dye1 in the extracellular compartment. Therefore, the overall fluorescenceof the system increases as the fluorescent dye is transported into thecells. In the presence of an inhibitor of SERT, uptake of the dye isreduced, and therefore, the fluorescence is also decreased, allowingthis inhibition to be quantified.

TABLE 14 Inhibition of SERT by compounds. SERT IC₅₀ SERT % InhibitionCompound (nM) @ Max Dose DMT 2,962 67.92 5-MeO-DMT 7,020 68.07 psilocin2,035 88.15 1 750.4 75.35 2 9,131 62.06 4 418.9 77.45 6 3,268 84.02

Example 20. Serotonin Release Activity in Synaptosomes

Disclosed compounds were assessed for their ability to release serotonin(5-HT) from rat synaptic vesicles (Table 15). Fluorinated Compound 4 wasa much more potent serotonin releaser than its non-fluorinatedcounterpart Compound 2.

Test Compounds. Compound 4 was prepared as described above. All othercompounds were commercially obtained.

Synaptosome 5-HT Release Assay. Synaptosome release assays wereconducted according to modifications of previously described procedures(Partilla et al. (2016). Interrogating the Activity of Ligands atMonoamine Transporters in Rat Brain Synaptosomes. In NeurotransmitterTransporters (pp. 41-52). Springer.). Briefly, synaptosomes wereprepared from rat brains. Male Sprague-Dawley rats were renderedunconscious with CO₂ and their brains were immediately removed. Thecerebella were discarded and the whole brains (minus striatum) wereplaced in ice-cold 0.32 M sucrose (10 mL per brain) and gentlyhomogenized by hand. The homogenate of each brain was centrifuged at1,000×g at 4° C. for 10 mins and the resulting supernatant was dilutedwith ice-cold 0.32 M sucrose to a total volume of 10 mL to provide thesynaptosome solution. Synaptosomes were then preloaded with 5 nM[³H]5-HT in the presence of selective uptake inhibitors of DAT (50 nMGBR12935), NET (100 nM nomifensine), and VMAT2 (1 μM reserpine) in Krebsphosphate buffer (KPB). The incubations were allowed to reachequilibrium for 2 h at 25° C. For the release reactions, 425 μL ofpreloaded synaptosomes were added to test tubes containing 75 μL of testdrugs diluted in KPB containing 1 mg/mL BSA. After 10 mins, the releasereaction was stopped using a cell harvester by rapid vacuum filtrationover GF/B filter paper presoaked in wash buffer (10 mM Tris-HCl, pH 7.4,150 mM NaCl) and the filters were washed with additional wash buffer.Filters were dried for 1 h at 60° C. and retained radioactivity wasquantified using a MicroBeta 2 liquid scintillation counter. The amountof retained radioactivity was inversely proportional to the extent ofrelease.

TABLE 15 Effect of compounds on 5-HT release from rat synaptosomes. 5-HTRelease EC₅₀ % Release @ Max Dose Compound (nM) (10 μM) DMT 80.76 80.772 182.7 71 4 8.426 71.36

Example 21. Synthesis of Additional Compounds

Additional disclosed compounds may be prepared by standard methods knownto those skilled in the art of organic synthesis, for example, thosepresented in Examples 1-3 and described elsewhere herein.

What is claimed is:
 1. A pharmaceutical composition comprising acompound represented by:

or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable adjuvant or carrier.
 2. (canceled)
 3. A method of treating amood disorder comprising administering a therapeutically effectiveamount of a compound represented by:

or a pharmaceutically acceptable salt thereof to a subject in needthereof.
 4. The method of claim 3, wherein the mood disorder is selectedfrom the group consisting of depressive disorders and bipolar disorders.5. The method of claim 3, wherein the mood disorder is a depressivedisorder.
 6. The method of claim 3, wherein the mood disorder is atreatment-resistant depressive disorder.
 7. The method of claim 3,wherein the mood disorder is selected from the group consisting of majordepressive disorder, persistent depressive disorder, postpartumdepression, premenstrual dysphoric disorder, seasonal affectivedisorder, psychotic depression, disruptive mood dysregulation disorder,substance/medication-induced depressive disorder, and depressivedisorder due to another medical condition.
 8. The method of claim 3,wherein the mood disorder is selected from the group consisting of asubstance-related disorder, a substance-use disorder, and an anxietydisorder. 9-10. (canceled)
 11. The method of claim 3, wherein the mooddisorder is selected from the group consisting of obsessive-compulsiveand related disorders, trauma- and stressor-related disorders, feedingand eating disorders, borderline personality disorder,attention-deficit/hyperactivity disorder, and autism spectrum disorder.12. The method of claim 3, wherein the method comprises administeringabout 0.5 mg to 150 mg of the compound. 13-18. (canceled)
 19. The methodof claim 3, wherein the method provides improvement in at least onesymptom selected from the group consisting of sadness or lethargy orlassitude, depressed mood, inability to feel, anxious worried feelings,fears, feeling tense, feeling restlessness, diminished interest in allor nearly all activities, difficulty initiating activities, significantincreased or decreased appetite leading to weight gain or weight loss,insomnia, irritability, fatigue, feelings of worthlessness or lowself-esteem, strongly held negative beliefs or pessimistic thoughtsabout self, others or world, feelings of helplessness, inability toconcentrate or distractibility, recurrent thoughts of death or suicide,feelings of guilt, memory complaints, difficulty experiencing positivefeelings, feeling cut off or distant from people, hypervigilance, risktaking behavior, avoidance of thoughts about a stressful or traumaticevent, pains and aches, ruminations and obsessive thoughts, compulsivebehaviors, talking to people you don't know well or strangers, beingcenter of attention, disturbing intrusive thoughts, can't get throughweek without drug use, guilty about drug use, problems with friends orfamily due to drug use, and withdrawal symptoms due to drug use. 20.(canceled)
 21. The method of claim 3, wherein the compound isadministered from one to four times per day.
 22. (canceled)
 23. A methodof treating a mood disorder comprising administering to a patient inneed thereof a pharmaceutical composition comprising an effective amountof a compound represented by:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 24. The method of claim 23, wherein the mooddisorder is selected from the group consisting of depressive disordersand bipolar disorders.
 25. The method of claim 23, wherein the mooddisorder is a depressive disorder.
 26. The method of claim 23, whereinthe mood disorder is a treatment-resistant depressive disorder.
 27. Themethod of claim 23, wherein the mood disorder is selected from the groupconsisting of major depressive disorder, persistent depressive disorder,postpartum depression, premenstrual dysphoric disorder, seasonalaffective disorder, psychotic depression, disruptive mood dysregulationdisorder, substance/medication-induced depressive disorder, anddepressive disorder due to another medical condition.
 28. The method ofclaim 23, wherein the mood disorder is selected from the groupconsisting of a substance-related disorder, a substance-use disorder,and an anxiety disorder. 29-30. (canceled)
 31. The method of claim 23,wherein the mood disorder is selected from the group consisting ofobsessive-compulsive and related disorders, trauma- and stressor-relateddisorders, feeding and eating disorders, borderline personalitydisorder, attention-deficit/hyperactivity disorder, and autism spectrumdisorder.
 32. The method of claim 23, wherein the method comprisesadministering about 0.5 mg to 150 mg of the compound. 33-34. (canceled)35. The method of claim 23, wherein the method provides improvement inat least one symptom selected from the group consisting of sadness orlethargy or lassitude, depressed mood, inability to feel, anxiousworried feelings, fears, feeling tense, feeling restlessness, diminishedinterest in all or nearly all activities, difficulty initiatingactivities, significant increased or decreased appetite leading toweight gain or weight loss, insomnia, irritability, fatigue, feelings ofworthlessness or low self-esteem, strongly held negative beliefs orpessimistic thoughts about self, others or world, feelings ofhelplessness, inability to concentrate or distractibility, recurrentthoughts of death or suicide, feelings of guilt, memory complaints,difficulty experiencing positive feelings, feeling cut off or distantfrom people, hypervigilance, risk taking behavior, avoidance of thoughtsabout a stressful or traumatic event, pains and aches, ruminations andobsessive thoughts, compulsive behaviors, talking to people you don'tknow well or strangers, being center of attention, disturbing intrusivethoughts, can't get through week without drug use, guilty about druguse, problems with friends or family due to drug use, and withdrawalsymptoms due to drug use. 36-37. (anceled)